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Human Molecular Genetics 2007 16(R2):R183-R194; doi:10.1093/hmg/ddm159
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Parkinson's disease

Bobby Thomas* and M. Flint Beal

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, A-501, New York, NY 10021, USA

* To whom correspondence should be addressed. Tel: +1 2127465341; Fax: +1 2127468276; Email: bot2003{at}med.cornell.edu

Received May 30, 2007; Revised May 30, 2007; Accepted June 20, 2007


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATHOGENIC MUTATIONS IN...
 PARK1 ({alpha}-SYNUCLEIN)
 PARK2 (PARKIN)
 PARK7 (DJ-1)
 PARK6 (PINK1)
 PARK8 (LRRK2)
 MITOCHONDRIAL DYSFUNCTION AND...
 CONCLUSION
 REFERENCES
 
Parkinson's disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. Clinical manifestations of this complex disease include motor impairments involving resting tremor, bradykinesia, postural instability, gait difficulty and rigidity. Current medications only provide symptomatic relief and fail to halt the death of dopaminergic neurons. A major hurdle in development of neuroprotective therapies are due to limited understanding of disease processes leading to death of dopaminergic neurons. While the etiology of dopaminergic neuronal demise is elusive, a combination of genetic susceptibilities and environmental factors seems to play a critical role. The majority of PD cases are sporadic however, the discovery of genes linked to rare familial forms of disease (encoding {alpha}-synuclein, parkin, DJ-1, PINK-1 and LRRK2) and studies from experimental animal models has provided crucial insights into molecular mechanisms in disease pathogenesis and identified probable targets for therapeutic intervention. Recent findings implicate mitochondrial dysfunction, oxidative damage, abnormal protein accumulation and protein phosphorylation as key molecular mechanisms compromising dopamine neuronal function and survival as the underlying cause of pathogenesis in both sporadic and familial PD. In this review we provide an overview of the most relevant findings made by the PD research community in the last year and discuss how these significant findings improved our understanding of events leading to nigrostriatal dopaminergic degeneration, and identification of potential cell survival pathways that could serve as targets for neuroprotective therapies in preventing this disabling neurological illness.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATHOGENIC MUTATIONS IN...
 PARK1 ({alpha}-SYNUCLEIN)
 PARK2 (PARKIN)
 PARK7 (DJ-1)
 PARK6 (PINK1)
 PARK8 (LRRK2)
 MITOCHONDRIAL DYSFUNCTION AND...
 CONCLUSION
 REFERENCES
 
Parkinson's disease (PD) was first described in the essay entitled, ‘An Essay of the Shaking Palsy’ by James Parkinson in 1817. PD is a devastating degenerative neurological illness without cure affecting 1–2% of the ‘over 50’ population with a current estimation of 1.5 million in the US alone. The neuropathological hallmarks are characterized by progressive and profound loss of neuromelanin containing dopaminergic neurons in the substantia nigra pars compacta (SNpc) with presence of eosinophillic, intracytoplamic, proteinaceous inclusions termed as Lewy bodies (LB) and dystrophic Lewy neurites in surviving neurons (1). Although, neuronal loss in SNpc is pronounced there is widespread neurodegeneration in the central nervous system (CNS) with the pars compacta being involved in midstages of the disease (2). Clinical features of PD include motor impairments involving resting tremor, bradykinesia, postural instability and rigidity along with non-motoric symptoms like autonomic, cognitive and psychiatric problems. The molecular pathways leading to this pathological picture and concomitant clinical syndromes are obscure, but it is believed that it may result from an environmental factor, a genetic causation or a combination of the two. Epidemiological studies reveal that < 10% of PD has a strict familial etiology while majority of cases are sporadic. The discovery of genes linked to rare familial forms of PD during the last decade have confirmed the role of genetics in development of PD, and provided vital clues in understanding molecular pathogenesis of the common sporadic illness. These genetic breakthroughs provide us with unique avenues to pursue the pathologic mechanisms leading to disease development and help us identify probable targets for developing neuroprotective therapies, which may revolutionize the treatment of this debilitating disorder.


   PATHOGENIC MUTATIONS IN PARKINSON'S DISEASE PATHOGENESIS
TOP
 ABSTRACT
 INTRODUCTION
 PATHOGENIC MUTATIONS IN...
PARK1 ({alpha}-SYNUCLEIN)
 PARK2 (PARKIN)
 PARK7 (DJ-1)
 PARK6 (PINK1)
 PARK8 (LRRK2)
 MITOCHONDRIAL DYSFUNCTION AND...
 CONCLUSION
 REFERENCES
 
Numerous attempts have been made to resolve the etiology of PD since its first description in 1817. Until the end of last century the influence of heredity was controversial however, identification of mutations in several genes responsible for Mendelian forms of PD confirms the role of genetics in disease development. The precise relationship of these familial linked genes to the more common sporadic illness is currently uncertain, however shared pathophysiologies among the two disease entities are parkinsonism with nigrostriatal dopaminergic degeneration suggesting involvement of common pathogenic mechanisms (3). Understanding these common disease-modifying pathways will promote our knowledge of the specific molecular aspects that lead to nigrostriatal degeneration in PD. Several genetic loci are identified for PD (Table 1), however, there are five clearly defined genetic causes of PD. Here, we discuss our current understanding of these gene products linked to monogenic forms of PD (PARK1, 2, 6, 7 and 8) with an emphasis on their normal function and pathogenic dysfunction contributing to disease pathogenesis.


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  		Table 1. Gene loci identified for Parkinson's disease

 

   PARK1 ({alpha}-SYNUCLEIN)
TOP
 ABSTRACT
 INTRODUCTION
 PATHOGENIC MUTATIONS IN...
 PARK1 ({alpha}-SYNUCLEIN)
PARK2 (PARKIN)
 PARK7 (DJ-1)
 PARK6 (PINK1)
 PARK8 (LRRK2)
 MITOCHONDRIAL DYSFUNCTION AND...
 CONCLUSION
 REFERENCES
 
{alpha}-Synuclein is a natively unfolded presynaptic protein believed to play a role in synaptic vesicle recycling, storage and compartmentalization of neurotransmitters and associates with vesicular and membranous structures (4–6). Structurally, {alpha}-synuclein consists of an N-terminal amphipathic region, a hydrophobic middle region (containing the non-amyloid-ß component domain) and an acidic C-terminal region. Three missense mutations in {alpha}-synuclein gene (A53T, A30P and E46K) (7–9), and in addition to genomic triplications of a region of {alpha}-synuclein gene are associated with autosomal dominant PD (10).

{alpha}-Synuclein has an increased propensity to aggregate due to its hydrophobic non-amyloid-ß component domain. The presence of fibrillar {alpha}-synuclein as a major structural component of LB in PD suggests a role of aggregated {alpha}-synuclein in disease pathogenesis (11). Recent studies provide compelling evidence of non-amyloid-ß component domain and truncated form of {alpha}-synuclein in mediating neurodegeneration in vivo. Overexpression of {alpha}-synuclein lacking residues 71–82 failed to aggregate and form oligomeric species in flies resulting in an absence of dopaminergic pathology. Contrary to this expression of a truncated version of {alpha}-synuclein, containing the non-amyloid ß-component induced increased aggregation into large inclusions bodies, increased accumulation of high molecular weight {alpha}-synuclein species and demonstrated enhanced dopaminergic neurotoxicity in flies (12). This was supported by another study where mice expressing C-terminally truncated human {alpha}-synuclein (containing residues 1–120) under a rat tyrosine hydroxylase promoter on mouse {alpha}-synuclein null background developed progressive loss of nigral dopaminergic neurons with pathological inclusions, and associated behaviors suggesting a critical role of C-terminal truncation of {alpha}-synuclein in aggregation and dopaminergic toxicity in vivo (13). This suggests that C-terminal of {alpha}-synuclein is an important regulator of its aggregation in vivo and pathogenic {alpha}-synuclein mutations in PD may enhance C-terminal truncation-induced aggregation (14). In addition, a pathological modification involving phosphorylation of Ser129 in {alpha}-synuclein promotes aggregation, and that Ser129 phosphorylated {alpha}-synuclein is a major component of LB (15,16). Interesting new findings suggests that G-protein-coupled receptor kinase 5 is responsible for catalyzing Ser129 phosphorylation of {alpha}-synuclein promoting formation of soluble oligomers and aggregates of {alpha}-synuclein (17). Recently, it was demonstrated that insufficiency of Sept4, a pre-synaptic scaffold protein involved in dopaminergic neurotransmission can enhance Ser-129 phosphorylated {alpha}-synuclein aggregation and toxicity in vivo, while a direct association of Sept4 with {alpha}-synuclein prevented Ser129 phosphorylation and {alpha}-synuclein self aggregation in vitro (18). However, the pathological modification of phosphorylated Ser129 of {alpha}-synuclein seems to be selective for neurons, and not for platelets from PD and multiple system atrophy patients (19). Presently, it is unclear whether accumulation of misfolded proteins that lead to LB-like inclusions are toxic or protective in PD. Pharmacological compounds known to promote inclusion formation seems to protect against {alpha}-synuclein toxicity (20). Using a protein aggregate filtration assay a recent study demonstrates that abundant presynaptic terminal associated {alpha}-synuclein aggregates are responsible for synaptic pathology and neurodegeneration, in contrast to {alpha}-synuclein aggregates from LBs in postmortem brains from dementia with Lewy body disease (DLBD), supporting a less prominent role of LBs in toxicity (21).

Mechanisms by which abnormal processing and accumulation of {alpha}-synuclein disrupt basic cellular functions leading to dopaminergic neurodegeneration are intensely studied. One of the earliest defects following {alpha}-synuclein accumulation in vivo is blockade of endoplasmic reticulum to golgi vesicular trafficking causing ER stress (22). Furthermore, transgenic mice expressing human A53T {alpha}-synuclein develop mitochondrial pathology (23,24) providing a crucial role of {alpha}-synuclein in modulating mitochondrial function in neurodegeneration. This may be due to the fact that {alpha}-synuclein is a modulator of oxidative damage, since mice lacking {alpha}-synuclein are resistant to mitochondrial toxins (25), while nigral dopaminergic neurons are vulnerable to degeneration and mitochondrial dysfunction following parkinsonian neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in human {alpha}-synuclein transgenic mice (26,27). In addition, ß-synuclein seems to protect {alpha}-synuclein-induced toxicity by reducing {alpha}-synuclein protein expression (28), by blocking development of pore-like oligomers of {alpha}-synuclein (29) and promoting cell survival by activation of Akt signaling (30) (Thomas et al., unpublished observation). Furthermore, mutant {alpha}-synuclein (A53T and A30P) overexpression increases cytosolic catecholamine concentrations leading to disruption of vesicular pH and normal functioning, and facilitate toxicity of oxidized catechol metabolites implicating selective degeneration in PD (31,32). Biochemical abnormalities in {alpha}-synuclein has also been shown to activate stress-signaling protein kinases (33), affect age-related decrease in neurogenesis (34), impair microtubule-dependent trafficking (35), reduce intercellular communications at gap junctions (36) and inhibit histone acetylation in the nucleus to promote toxicity (37). These pathophysiological aspects are detrimental to normal functioning of dopaminergic neurons and provide implications for disease pathogenesis in {alpha}-synuclein-induced PD.


   PARK2 (PARKIN)
TOP
 ABSTRACT
 INTRODUCTION
 PATHOGENIC MUTATIONS IN...
 PARK1 ({alpha}-SYNUCLEIN)
 PARK2 (PARKIN)
PARK7 (DJ-1)
 PARK6 (PINK1)
 PARK8 (LRRK2)
 MITOCHONDRIAL DYSFUNCTION AND...
 CONCLUSION
 REFERENCES
 
The parkin gene encodes a 465 amino acid protein containing an N-terminal ubiquitin like domain, a central linker region and C-terminal RING domain consisting of two RING finger motifs separated by an in between RING domain. Parkin functions as an E3 ubiquitin protein ligase similar to other RING finger containing proteins by targeting misfolded proteins to the ubiquitn proteasome pathway for degradation, and the loss of its E3 ligase activity due to mutations lead to autosomal recessive early-onset PD (38–40). Mutations in the parkin gene are a major cause of autosomal recessive early onset PD. Several putative substrates of parkin have been identified and the accumulation of one or several of these substrates is implicated in neurodegeneration (41).

Parkin functions as a multipurpose neuroprotective protein in a variety of toxic insults crucial for dopamine neuron survival (42). New research has identified neuroprotective mechanisms mediated by parkin. Recent studies suggest that parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor-kappaB signaling, whereas parkin mutants failed to stimulate this pathway (43). Furthermore, the UBL domain of parkin interacts with ubiquitin interacting motifs (UIM) of Eps15 [an adaptor protein involved in epidermal growth factor receptor (EGFR) endocytosis and trafficking] and ubiquitinates in a proteasome-independent manner. Parkin interferes with the ability of Eps15 UIMs to bind ubiquitinated EGFR delaying EGFR internalization and degradation to promote phosphatidylinositol 3-kinase/Akt cell survival signaling (44). Parkin also seems to modulate key mitochondrial functions which include, a role in mitochondrial morphogenesis during spermiogenesis (45), and enhancing mitochondrial biogenesis in proliferating cells through transcription and replication of mitochondrial DNA (46). Parkin also rescues mitochondrial dysfunction, muscle degeneration and dopaminergic loss in flies due to inactivation of a putative mitochondrial serine/threonine kinase (PINK1), that cause autosomal recessive PD (47–49). This is consistent with increased susceptibility of mesencephalic dopaminergic neurons in cultures to mitochondrial complex I inhibitor rotenone-induced death (50). In addition, a recent study demonstrates {alpha}-synuclein-induced mitochondrial dysfunction is further enhanced due to lack of parkin activity in vivo implicating crucial role of parkin in modulating mitochondrial functions in {alpha}-synuclein-induced PD (23). Post-translational modification of parkin either due to oxidative or nitrosative stress also compromise its protective function by impairing the E3 ligase activity (51,52). Dopaminergic neurons are especially vulnerable to activation of the Cyclin-dependent kinase 5 (Cdk5) (53). Cdk5 interacts and phosphorylates parkin at Ser131 of the linker region. This modification blocks autoubiquitylation leading to parkin aggregation both in vitro and in vivo (54). Both disease-specific mutants of parkin and RING-IBR-RING type ubiquitin ligases similar to parkin are susceptible to solubility alterations due to oxidative damage (55,56). Recent studies also provide important new insights for the first time on the role of mutant parkin in vivo. Age-dependent dopaminergic neurodegeneration and motor impairments are observed due to expression of mutant human parkin and not wild-type parkin in flies implying a toxic gain of function mechanism (57). This is in contrast to lack of nigral dopaminergic degeneration in mouse models generated by targeted deletion of parkin representing loss of function phenomenon (58). Surprisingly, catecholaminergic neurons from parkin knockout mice fail to show increased susceptibility to neurodegeneration against neurotoxins (59,60) and human {alpha}-synuclein-induced disease (23,61), contrary to this mesencephalic dopaminergic neurons from parkin knockout mice show resistance to nitric oxide-induced toxicity by compensatory increase in glutathione levels (62). These findings suggest that although parkin is considered as a multipurpose neuroprotective agent, its neuroprotective efficiency is very selective and identification of the specific neuroprotective pathways that are affected due to parkin deficiency will help identify its role in PD pathogenesis.


   PARK7 (DJ-1)
TOP
 ABSTRACT
 INTRODUCTION
 PATHOGENIC MUTATIONS IN...
 PARK1 ({alpha}-SYNUCLEIN)
 PARK2 (PARKIN)
 PARK7 (DJ-1)
PARK6 (PINK1)
 PARK8 (LRRK2)
 MITOCHONDRIAL DYSFUNCTION AND...
 CONCLUSION
 REFERENCES
 
Loss-of-function mutations in the DJ-1 locus are associated with rare forms of autosomal recessive early-onset parkinsonism (63). DJ-1 mutations account for 1–2% of all early-onset PD (64), with a number of different pathogenic mutations, including exonic deletions, truncations and homozygous and heterozygous point mutations. DJ-1 is a highly conserved protein of 189 amino acids that belongs to the DJ-1/Thi/PfpI protein super family. It has ubiquitous expression in a variety of mammalian tissues including brain and localized to mitochondria (65,66). DJ-1 is a homodimeric protein originally identified as an oncogene with proposed roles in sperm maturation and fertilization. Association of DJ-1 through pathogenic mutations in familial PD has identified its novel functions that shed light in disease pathogenesis. These include proposed antioxidant, transcriptional co-activator and chaperone activity.

Many lines of evidence suggest that DJ-1 functions as an antioxidant protein. Oxidative stress leads to an acidic shift in the DJ-1 isoelectric point by oxidation of Cys106 which can be converted to cysteine sulfinic acid (Cys-SO2H) (67). Because of its inherent ability to undergo self oxidation to eliminate H2O2 it may function as a scavenger of reactive oxygen species (ROS) (68). Overexpression of wild-type DJ-1 both in cell culture and to dopaminergic neurons in vivo protects against wide variety of toxic injury due to oxidative stress (68–70). The apparent antioxidant action appears to be due to the ability of DJ-1 to stabilize the antioxidant transcriptional master regulator Nrf2 (nuclear factor erythroid 2-related factor) by preventing association with its inhibitor, Keap1 and ubiquitination of Nrf2 (71). This is consistent with the ability of DJ-1 to increase cellular glutathione levels by activating the glutamate cysteine ligase (72). DJ-1 also functions like a redox-dependent chaperone to inhibit {alpha}-synuclein aggregation and subsequent death (73,74). Furthermore, it associates with parkin during oxidative stress suggesting a common role in neuroprotection (75). Familial PD-linked mutations in DJ-1 are considered to cause nigral degeneration through loss-of-function mechanism consistent with the recessive inheritance. The classic L166P mutation in DJ-1 prevents its dimerization by unfolding its C-terminal region leading to decreased steady-state levels due to accelerated protein degradation by the proteasome (76). Recently, familial substitutions (M26I and E64D) together with H2O2-induced cysteine 106 oxidation and cleavage have been shown to destabilize DJ-1 (77,78). Furthermore, mass spectrometric identification of methionine oxidized DJ-1 in sporadic PD brains suggests a role of methionine oxidation in disease pathogenesis (79). Mouse models lacking DJ-1 develop age-dependent motor deficits, hypokinesia and dopaminergic dysfunction with no neuronal loss (80,81). Nigrostriatal dopaminergic neurons in these mice show increased vulnerability to the parkinsonian neurotoxin MPTP via an unknown mechanism (82). Increased vulnerability in DJ-1 knockout mice could be due to increased p53 and Bax expression (83), deficits in phase II detoxification enzyme NQO1 (NADPH quinone oxidoreductase 1) (71), irreversible membrane potential changes due to impaired Na+/K+ ATPase (84), defective phosphatidylinositol 3-kinase/Akt signaling (85), and inability of the death protein Daxx to inhibit ASK1- (apoptosis signal regulating kinase 1) induced cell death (86). Of particular significance to dopaminergic neuronal function is the ability of DJ-1 to transcriptionally upregulate tyrosine hydroxylase expression by suppressing the sumoylation of pyrimidine tract-binding protein-associated splicing factor (87). These studies conclusively prove that DJ-1 plays a crucial role in maintenance and survival of dopaminergic neurons. Characterization of the molecular details of DJ-1s role in dopaminergic neuronal function will help provide us with novel insights into its role in disease pathogenesis.


   PARK6 (PINK1)
TOP
 ABSTRACT
 INTRODUCTION
 PATHOGENIC MUTATIONS IN...
 PARK1 ({alpha}-SYNUCLEIN)
 PARK2 (PARKIN)
 PARK7 (DJ-1)
 PARK6 (PINK1)
PARK8 (LRRK2)
 MITOCHONDRIAL DYSFUNCTION AND...
 CONCLUSION
 REFERENCES
 
Mutations in the PINK1 [phosphatase and tensin (PTEN) homolog-induced putative kinase 1] gene were identified to cause early-onset familial PD (88). PINK1 mutation frequency varies between 1 and 9% with considerable variation among different ethnic groups (89). PINK1 is a 581 amino acid protein that contains an N-terminal mitochondrial targeting sequences and a highly conserved protein kinase domain similar to serine/threonine kinases of the Ca2+ calmodulin family. It has a ubiquitous and punctate expression pattern suggesting mitochondrial localization (90). Very little is known about the precise function of PINK1 although its mitochondrial localization, presence of kinase domain with identification of majority of mutations in the kinase domain and regions close to it suggest a role in mitochondrial dysfunction, protein stability and kinase pathways in pathogenesis of PD (91,92). No putative substrates to the kinase have been identified till date, however PINK1 has been shown to undergo autophosphorylation and phosphorylate an artifical substrate histone H1. C-terminus truncation of PINK1 and disease-related mutations downregulate its serine/threonine kinase activity and confer different autophosphorylation patterns suggesting the importance of its kinase activity in mitochondrial function (93,94). Recent study emphasize the role of PINK1 in mitochondrial biogenesis and demonstrate that human PINK1 locus is regulated by non-coding naturally occurring antisense RNA in vivo implying for the first time, a role of non-coding RNAs in regulating functions of familial PD-linked genes (95).

In vitro studies suggest that overexpression of wild-type PINK1 can prevent staurosporine-induced, mitochondrial cytochrome c release and subsequent apoptosis by caspase 3 activation, which is abrogated by familial PD-linked PINK1 mutants (96). This is consistent with increased vulnerability to dopaminergic SH-SY5Y cells to the mitochondrial toxins rotenone and MPP+ (1-methyl-4-phenyl-pyridinium ion) following suppression of PINK1 function by siRNA (97), or due to expression of PINK1 disease mutants (98). Proteasomal stress enables PINK1 to undergo altered cleavage impairing its function (99), a phenomenon that may enable it to accumulate in LBs, whereas mutations affect protein stability (92,100). In vivo PINK1 loss of function either due to its inactivation by siRNA or due to expression of disease-causing mutations leads to muscle and dopaminergic degeneration as a consequence of mitochondrial dysfunction in flies. Interestingly, this degenerative phenotype was rescued by overexpression of the ubiquitin E3 ligase parkin, implicating the importance of both parkin and PINK1 in regulating mitochondrial physiology and survival in flies (47–49). At this juncture, the functional implications of parkin and PINK1 interaction seem to be unclear, however loss of PINK1 function might impair proteasomal activity due to mitochondrial dysfunction. Consistent with mitochondrial dysfunction, immortalized lymphoblasts from patients with G309D–PINK1 mutations show increased lipid peroxidation and defects in mitochondrial complex I activity, and a compensatory increase in mitochondrial superoxide dismutases and glutathione (101). Furthermore, overexpression of human SOD1 prevented dopaminergic neuronal loss due to PINK1 inactivation in flies suggesting that mitochondrial dysfunction modulates oxidative damage pathways (102). This phenomenon gains further support from the fact that oxidative damage due to PINK1 dysfunction recruits the antioxidant DJ-1 in the pathway for rescue by maintaining steady-state levels of PINK1 through physical interaction and overexpression of DJ-1 (98). At this stage its premature to conclude the physiological function of PINK1 through its direct interaction with both parkin and DJ-1. However, the interaction suggests involvement of three different gene products causing familial PD in sharing common pathways for PD pathogenesis. Future studies on identification of PINK1 substrates and detailed characterization of in vivo models of PINK1 knockouts will shed light on its normal physiological function and provide us important clues on how pathogenic mutations mediate disease progression and pathogenesis.


   PARK8 (LRRK2)
TOP
 ABSTRACT
 INTRODUCTION
 PATHOGENIC MUTATIONS IN...
 PARK1 ({alpha}-SYNUCLEIN)
 PARK2 (PARKIN)
 PARK7 (DJ-1)
 PARK6 (PINK1)
 PARK8 (LRRK2)
MITOCHONDRIAL DYSFUNCTION AND...
 CONCLUSION
 REFERENCES
 
Mutations in the leucine-rich repeat kinase 2 (LRRK2) or dardarin cause autosomal dominant PD (103,104). This gene has obtained considerable attention because of the presence of LRRK2 mutations beyond familial cases of disease with evidence that mutations occur at high frequency in 1–7% of patients from European origin and 20–40% in Ashkenazi Jews and North African Arabs, although the prevalence varies markedly between populations (105). LRRK2 encodes a 2527 amino acid multidomain, 280 kDa protein belonging to ROCO protein family that includes a Rho/Ras-like GTPase domain, a protein kinase domain of the MAPKKK family, as well as a WD40-repeat and a leucine-rich repeat domains. An additional domain C-terminal to the GTPase domain, termed COR (for carboxy-terminal of Ras), is of unknown function. Point mutations have been found in almost all of the identified domains. The presence of mutations in several different domains, as well as the lack of deletions or truncations, along with dominant inheritance, is consistent with a gain-of-function mechanism. The precise physiological role of this protein is unknown but presence of multiple functional domains suggesting involvement in wide variety of functions.

A series of studies were conducted to identify the intracellular and tissue-specific location of LRRK2 both in cell culture and in vivo to identify a probable function based on its localization. The majority of forebrain structures including nigrostriatal dopaminergic neurons express LRRK2 and it seems to be predominantly cytoplasmic especially in the golgi apparatus, synaptic vesicles, plasma membrane, lysosomes and associates with the outer mitochondrial membrane (106–110). Deletion mutants of LRRK2 homolog in Caenorhabditis elegans LRK-1, led to depletion of synaptic vesicle proteins in dendritic endings of neurons determining its role in polarized sorting of synaptic vesicle proteins to axons (111). Recent studies also show the ability of LRRK2 to associate with lipid rafts, localize to LBs and regulate neurite length and branching (112–114). These suggest that LRRK2 modulates synaptic vesicle recycling, neurite outgrowth and functions inherent to golgi, lysosomes and mitochondria, dysfunctions of which may compromise dopamine neuron survival (115).

The domain structure of LRRK2 protein suggests a wide variety of functions that could be responsible for the pleomorphic pathology found in the mutation carriers. There are several missense mutations identified to date, of which the G2019S mutation is the most prevalent (116). The G2019S and the nearby I2020T mutation are located at the N-terminal portion of the activation loop in kinase domain. These mutations are associated with increased kinase activity of LRRK2 assessed by autophosphorylation or phosphorylation of generic substrate myelin basic protein when compared with either wild-type LRRK2, a kinase dead mutant, or equivalent mutations in paralogous kinase LRRK1 (117–123). Several studies suggest that the kinase activity of LRRK2 is regulated by GTP via the intrinsic GTPase ROC domain of LRRK2 (120–122). This is supported by the fact that mutations in the GTPase ROC domain (R1441C, T1348N) disrupts GTP binding and hydrolysis abolishing the kinase activity (122,124). The LRRK2 kinase domain provides sequence homology to mixed lineage kinases with specificity for serine/threonine kinase or tyrosine kinase. In a recent study, in vitro autophosphorylation using thin-layer chromatography revealed kinase-dependent serine/threonine phosphorylation but not tyrosine phosphorylation suggesting that LRRK2 might function as a serine/threonine kinase and may not meet the criteria for mixed lineage kinase (121). It is becoming increasingly evident from multiple studies that kinase activity in LRRK2 due to disease-causing mutations affects cell viability due to apoptosis providing a direct role of pathological activation of LRRK2 kinase causing neurodegeneration (119–121,125,126). At this stage it is unclear how increased kinase activity affects signaling leading to disease pathogenesis in PD. Recent findings show significant alterations in phosphorylation of key proteins involved in MAPK signaling in leukocytes from patients with G2019S mutations implicating abnormal protein phosphorylation (127). Identification of physiological LRRK2 substrates and characterization of in vivo models of LRRK2 will help understand both physiological and pathological functions of LRRK2 affecting disease pathogenesis.


   MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE DAMAGE IN PARKINSON'S DISEASE PATHOGENESIS
TOP
 ABSTRACT
 INTRODUCTION
 PATHOGENIC MUTATIONS IN...
 PARK1 ({alpha}-SYNUCLEIN)
 PARK2 (PARKIN)
 PARK7 (DJ-1)
 PARK6 (PINK1)
 PARK8 (LRRK2)
 MITOCHONDRIAL DYSFUNCTION AND...
CONCLUSION
 REFERENCES
 
Multiple lines of evidence suggest a pathogenic role of oxidative damage and mitochondrial dysfunction in causing PD. Consistent deficits in the subunits and activity of mitochondrial complex I of the electron transport chain in blood platelets and SNpc of PD patients is a prominent phenomenon (128,129). Reduced complex I activity is also seen in cytoplasmic hybrid (cybrid) cell lines containing mitochondrial DNA from PD patients (130). Epidemiological studies reveal that exposure to pesticides, industrial wastes and environmental toxins are involved in disease pathogenesis in PD (131). A classic example is the accidental discovery of MPTP whose toxic metabolite MPP+, by selective uptake in dopaminergic neurons caused parkinsonism in designer-drug abusers due to mitochondrial dysfunction (132). Similar to MPTP, other complex I inhibitors like rotenone and paraquat-induced dopaminergic degeneration in rodents, suggesting central role of mitochondrial dysfunction in PD pathogenesis (133,134). Several studies provide support to the notion of mitochondrial dysfunction in the causation of PD (135). A recent study demonstrated that SNpc neurons have high amount of mitochondrial DNA (mtDNA) deletions in postmortem PD patients when compared with other neuronal populations in brain- and age-matched controls (136). A related study identified that nigral neurons from PD patients contain high levels of clonally expanded somatic mtDNA deletions leading to mitochondrial dysfunction (137). These human findings gain further support by a study where targeted deletion of mitochondrial transcription factor A (TFAM) in midbrain dopaminergic neurons led to progressive PD in mice, due to reduced mtDNA expression and respiratory chain deficiency (138). Furthermore, a surprisingly low mitochondrial mass observed in SNpc of mice might be a contributing factor to selective vulnerability of these neuronal populations to mitochondrial dysfunction (139). This suggests that factors which directly or indirectly modulate normal mitochondrial functioning can significantly compromise neuronal survivability suggesting its detrimental role in PD pathogenesis.

Nigrostriatal dopaminergic neurons in general are under tremendous oxidative stress probably due to redox cycling of catechols, leading to increased generation of detrimental ROS. Decrements in reduced glutathione levels in SNpc of pre-symptomatic PD suggest that oxidative damage occurs much earlier than the actual neuronal loss (140). Interplay between oxidative stress and mitochondrial dysfunction is further suggested by an impairment of mitochondrial complex I due to chronic depletion of antioxidant glutathione (141). Furthermore, PPARgamma coactivator 1alpha (PGC-1{alpha}), which is involved in mitochondrial biogenesis and respiration, is a modulator of ROS generation during oxidative stress (142). In a recent study it was demonstrated that PGC-1{alpha} is required for induction of many ROS detoxifying enzymes like glutathione peroxidase-1, catalase and manganese superoxide dismutase upon oxidative stress. Nigrostriatal dopaminergic neurons in mice lacking PGC-1{alpha} were more vulnerable to parkinsonian neurotoxin MPTP. Furthermore, overexpression of PGC-1{alpha} protected neural cells due to oxidative stress-induced death providing compelling evidence to the role of PGC-1{alpha} as a powerful regulator of ROS metabolism. The ability of PGC-1{alpha} to increase activity of mitochondrial electron transport chain while stimulating a broad anti-ROS program makes it an important target to limit the damage that has been associated with defective mitochondrial function and oxidative damage seen in several neurodegenerative diseases including PD (143). A recent study from postmortem brains suggests a prominent role of Nrf2/ARE signaling in PD pathogenesis (144). The leucine-zipper transcription factor Nrf2 regulates coordinated induction of antioxidant response element-(ARE) driven battery of cytoprotective genes, including a variety of both antioxidant and anti-inflammatory proteins (145). Oxidation of a critical cysteine in Keap 1 allows Nrf2 to translocate into the nucleus, where it then activates transcription of genes encoding phase II detoxification enzymes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferases (GST), glutamate-cysteine ligase (GCL), hemeoxygenase 1 (HO-1) and downregulates inflammatory enzymes like cycloxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and many others (146–148). Disruption of Nrf2 renders neuronal tissues more susceptible to death due to oxidative stress and mitochondrial dysfunction in Nrf2 knockout mice (149–151). Recent findings from our laboratory suggest that pharmacological activation of the Nrf2/ARE pathway rescue neurodegeneration in a mouse model of PD due to induction of antioxidant enzymes and downregulaion of inflammatory molecules like iNOS and COX-2. (Yang, Thomas et al., unpublished observations). Since both oxidative damage and inflammation are implicated in PD pathogenesis this pathway may serve as an important target for neurotherapeutics (152,153). Another promising pathway that has emerged in dopamine neuronal survival is the phosphatidylinositol 3-kinase/Akt pathway. A recent study demonstrates that overexpression of the oncoprotein Akt, protected against 6-OHDA-induced dopaminergic toxicity. Akt conferred pronounced neurotrophic effects on dopamine neurons of adult and aged mice, including increases in neuron size, and sprouting (154). In addition, our results also support the importance of Akt activation in dopaminergic neuronal survival via a selective regulatory mechanism involving modulation of ß-synuclein expression by {alpha}-synuclein in vivo (Thomas et al., unpublished observation). Furthermore, other familial PD-linked proteins, parkin (44), DJ-1 (85) and PINK1 (88) mediate cell survival through the Akt pathway supporting a pathogenic role of Akt regulation in PD.

Several genes associated with PD also link mitochondria and oxidative damage in disease pathogenesis. These include {alpha}-synuclein, parkin, DJ-1, PINK1 and LRRK2. Several direct or indirect pathogenic mechanisms enable familial PD-associated genes link to mitochondria. {alpha}-Synuclein, a major component of LB, seems to link abnormal protein degradation to oxidative stress and mitochondrial dysfunction. Mice overexpressing human A53T {alpha}-synuclein induce mitochondrial damage due to aberrant {alpha}-synuclein accumulation (24). We have shown that mice lacking {alpha}-synuclein are resistant to mitochondrial toxins like MPTP, 3-nitropropionic acid and malonate while overexpression of human {alpha}-synuclein in mice enhances vulnerability to mitochondrial toxin MPTP (25,26) (Thomas et al., unpublished observations). Parkin, an E3 ligase, seems to link the ubiquitin proteasome system, oxidative stress and mitochondrial dysfunction. Gene knockouts of parkin mouse and flies show increased oxidative stress and mitochondrial dysfunction (155,156). Parkin also prevents mitochondrial swelling, cytochrome c release and caspase activation which is abrogated due to parkin mutations and proteasome inhibitors (157). In proliferating cells, parkin localizes to mitochondria to associate with TFAM and enhances mitochondrial biogenesis (46). Oxidative and nitrosative modification of parkin either due to a dopamine quinone modification or S-nitrosylation impairs its ubiquitin E3 ligase activity to compromise its protective function (51,52). In addition, DJ-1 mutations link familial early-onset PD with mitochondrial dysfunction and oxidative stress. The inherent ability of DJ-1 to function as a sensor of oxidative stress and as an antioxidant supports this notion. Furthermore, mitochondrial localization of DJ-1 (66) and hypersensitivity to mitochondrial toxin like MPTP in DJ-1 knockout mice (82) provides substantial evidence on its role in mediating mitochondrial and oxidative stress-mediated neurodegeneration. A possible link to age-dependence in sporadic PD is further supported by increased oxidative inactivation of DJ-1 due to ageing and enhanced susceptibility to oxidative damage in flies (158). Discovery of PINK1, a mitochondrial kinase and the newly identified cytosolic kinase LRRK2 modulate a pathogenic role in mediating mitochondria-dependent death. Detailed description of these pathways of PINK1 and LRRK2 are described in PARK6 and PARK8 section of this review. Thus, it is becoming increasingly clear from multiple lines of studies that both oxidative damage and mitochondrial dysfunction takes a center stage in disease pathogenesis leading to sporadic and familial PD.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 PATHOGENIC MUTATIONS IN...
 PARK1 ({alpha}-SYNUCLEIN)
 PARK2 (PARKIN)
 PARK7 (DJ-1)
 PARK6 (PINK1)
 PARK8 (LRRK2)
 MITOCHONDRIAL DYSFUNCTION AND...
 CONCLUSION
REFERENCES
 
PD is a complex disease with multiple etiological factors involved in disease pathogenesis. Studies from familial PD-linked genes have enormously improved our understanding of disease development of the more common sporadic form of the disease. At this juncture there are several different pathways that are important in modulating pathogenic events leading to death of dopaminergic neurons in PD (Fig. 1). Interestingly, these pathways seem to converge on aspects that affect dopamine neuronal function and survival due to mitochondrial dysfunction, oxidative damage, abnormal protein accumulation and protein phosphorylation. Many familial-linked PD genes and experimental animal models provide an emerging role of Nrf2/ARE and phosphatidylinositol 3-kinase/Akt signaling pathway as a potential target for therapeutic interventions since, these two pathways seem to modify several common pathophysiological aspects. Future research will enable us to further dissect molecular details of various disease-modifying pathways and potential convergence if any, to establish a common pathogenic theme for the two different forms of disease entities. These will further enable us to better understand the etiology of disease and develop novel neuroprotective therapies targeting these common pathways.


Figure 1
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  		Figure 1. Common intersecting pathways underlying PD pathogenesis. Both environmental factors and mutations in familial PD-linked genes encoding {alpha}-synuclein, parkin, DJ-1, PINK1 and LRRK2 are associated with PD pathogenesis. These pathogenic mutations and environmental factors are known to cause disease due to mitochondrial dysfunction, oxidative damage, abnormal protein aggregation and protein phosphorylation compromising key roles of dopaminergic neuronal function and survival. Environmental factors similar to pesticides and toxins directly induce both oxidative damage and mitochondrial dysfunctions. {alpha}-Synuclein undergoes aggregation either due to pathogenic mutations or catechol oxidation which in turn compromise ubiquitin proteasome function (UPS), induce ER stress and cause mitochondrial dysfunction. Mitochondrial dysfunction and oxidative damage lead to deficits in ATP which may compromise UPS function promoting abnormal protein aggregation. ß-Synuclein is known to prevent {alpha}-synuclein aggregation through activation of Akt signaling. Parkin, an ubiquitin E3 ligase, promotes proteasomal degradation, increases mitochondrial biogenesis by activating mitochondrial transcription factor A (TFAM) and block PINK1-induced mitochondrial dysfunction, while pathogenic mutations, oxidative and nitrosative damage severely compromise its protective function. DJ-1 protects against oxidative stress, functions as a chaperone to block {alpha}-synuclein aggregation and protects against mitochondrial dysfunction. PINK1 seems to protect against mitochondrial dysfunction which is compromised due to pathogenic mutations, although the precise function of PINK1 in mitochondria still needs to be determined. LRRK2 seems to play a role in synaptic vesicle functions, neurite outgrowth, etc. Pathogenic mutations in LRRK2 cause abnormal protein phosphorylation which induce mitochondria-dependent cell death. In addition, a neuroprotective role of PGC-1{alpha} in preventing oxidative damage and mitochondrial dysfunction is suggested, whereas a pathogenic role of PI3kinase-Akt (phosphatidylinositol 3-kinase/Akt) and Nrf2/ARE signaling is implicated in PD pathogenesis. Familial PD-linked genes namely parkin, DJ-1 and PINK1 activate PI3 kinase-Akt signaling, while activation of Nrf2/ARE pathway prevents against oxidative damage and mitochondrial dysfunction promoting cell survival. Both PI3 kinase-Akt and Nrf2/ARE signaling could be explored as potential targets of therapeutic intervention in dopaminergic neuronal demise. Green arrows indicate promoting or activating effects while red lines with blunt ends indicate inhibitory effects.

 


   ACKNOWLEDGEMENTS
 
This work is supported by grants from National Institutes of Health, Michael J Fox Foundation for Parkinson's disease and the Department of Defense. The authors apologize for the inability to cite several articles due to space limitations.

Conflict of Interest statement. None declared.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATHOGENIC MUTATIONS IN...
 PARK1 ({alpha}-SYNUCLEIN)
 PARK2 (PARKIN)
 PARK7 (DJ-1)
 PARK6 (PINK1)
 PARK8 (LRRK2)
 MITOCHONDRIAL DYSFUNCTION AND...
 CONCLUSION
 REFERENCES
 

  1. Forno L.S. Neuropathology of Parkinson's disease. J. Neuropathol. Exp. Neurol. (1996) 55:259–272.[Web of Science][Medline]

  2. Braak H., Del Tredici K., Rub U., de Vos R.A., Jansen Steur E.N., Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging (2003) 24:197–211.[CrossRef][Web of Science][Medline]

  3. Hardy J., Cookson M.R., Singleton A. Genes and parkinsonism. Lancet Neurol. (2003) 2:221–228.[CrossRef][Web of Science][Medline]

  4. Abeliovich A., Schmitz Y., Farinas I., Choi-Lundberg D., Ho W.H., Castillo P.E., Shinsky N., Verdugo J.M., Armanini M., Ryan A., et al. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron (2000) 25:239–252.[CrossRef][Web of Science][Medline]

  5. Yavich L., Tanila H., Vepsalainen S., Jakala P. Role of alpha-synuclein in presynaptic dopamine recruitment. J. Neurosci. (2004) 24:11165–11170.[Abstract/Free Full Text]

  6. Yavich L., Jakala P., Tanila H. Abnormal compartmentalization of norepinephrine in mouse dentate gyrus in alpha-synuclein knockout and A30P transgenic mice. J. Neurochem. (2006) 99:724–732.[CrossRef][Web of Science][Medline]

  7. Polymeropoulos M.H., Lavedan C., Leroy E., Ide S.E., Dehejia A., Dutra A., Pike B., Root H., Rubenstein J., Boyer R., et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science (1997) 276:2045–2047.[Abstract/Free Full Text]

  8. Kruger R., Kuhn W., Muller T., Woitalla D., Graeber M., Kosel S., Przuntek H., Epplen J.T., Schols L., Riess O. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat. Genet. (1998) 18:106–108.[CrossRef][Web of Science][Medline]

  9. Zarranz J.J., Alegre J., Gomez-Esteban J.C., Lezcano E., Ros R., Ampuero I., Vidal L., Hoenicka J., Rodriguez O., Atares B., et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. (2004) 55:164–173.[CrossRef][Web of Science][Medline]

  10. Singleton A.B., Farrer M., Johnson J., Singleton A., Hague S., Kachergus J., Hulihan M., Peuralinna T., Dutra A., Nussbaum R., et al. {alpha}-Synuclein locus triplication causes Parkinson's disease. Science (2003) 302:841.[Free Full Text]

  11. Spillantini M.G., Crowther R.A., Jakes R., Hasegawa M., Goedert M. {alpha}-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies. Proc. Natl Acad. Sci. USA (1998) 95:6469–6473.[Abstract/Free Full Text]

  12. Periquet M., Fulga T., Myllykangas L., Schlossmacher M.G., Feany M.B. Aggregated alpha-synuclein mediates dopaminergic neurotoxicity in vivo. J. Neurosci. (2007) 27:3338–3346.[Abstract/Free Full Text]

  13. Tofaris G.K., Garcia Reitbock P., Humby T., Lambourne S.L., O'Connell M., Ghetti B., Gossage H., Emson P.C., Wilkinson L.S., Goedert M., et al. Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1–120): implications for Lewy body disorders. J. Neurosci. (2006) 26:3942–3950.[Abstract/Free Full Text]

  14. Li W., West N., Colla E., Pletnikova O., Troncoso J.C., Marsh L., Dawson T.M., Jakala P., Hartmann T., Price D.L., et al. Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations. Proc. Natl Acad. Sci. USA (2005) 102:2162–2167.[Abstract/Free Full Text]

  15. Anderson J.P., Walker D.E., Goldstein J.M., de Laat R., Banducci K., Caccavello R.J., Barbour R., Huang J., Kling K., Lee M., et al. Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J. Biol. Chem. (2006) 281:29739–29752.[Abstract/Free Full Text]

  16. Smith W.W., Margolis R.L., Li X., Troncoso J.C., Lee M.K., Dawson V.L., Dawson T.M., Iwatsubo T., Ross C.A. Alpha-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J. Neurosci. (2005) 25:5544–5552.[Abstract/Free Full Text]

  17. Arawaka S., Wada M., Goto S., Karube H., Sakamoto M., Ren C.H., Koyama S., Nagasawa H., Kimura H., Kawanami T., et al. The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson's disease. J. Neurosci. (2006) 26:9227–9238.[Abstract/Free Full Text]

  18. Ihara M., Yamasaki N., Hagiwara A., Tanigaki A., Kitano A., Hikawa R., Tomimoto H., Noda M., Takanashi M., Mori H., et al. Sept4, a component of presynaptic Scaffold and Lewy bodies, is required for the suppression of alpha-synuclein neurotoxicity. Neuron (2007) 53:519–533.[CrossRef][Web of Science][Medline]

  19. Shults C.W., Barrett J.M., Fontaine D. {alpha}-Synuclein from platelets is not phosphorylated at serine 129 in Parkinson's disease and multiple system atrophy. Neurosci. Lett. (2006) 405:223–225.[CrossRef][Web of Science][Medline]

  20. Bodner R.A., Outeiro T.F., Altmann S., Maxwell M.M., Cho S.H., Hyman B.T., McLean P.J., Young A.B., Housman D.E., Kazantsev A.G. Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington's and Parkinson's diseases. Proc. Natl Acad. Sci. USA (2006) 103:4246–4251.[Abstract/Free Full Text]

  21. Kramer M.L., Schulz-Schaeffer W.J. Presynaptic alpha-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J. Neurosci. (2007) 27:1405–1410.[Abstract/Free Full Text]

  22. Cooper A.A., Gitler A.D., Cashikar A., Haynes C.M., Hill K.J., Bhullar B., Liu K., Xu K., Strathearn K.E., Liu F., et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science (2006) 313:324–328.[Abstract/Free Full Text]

  23. Stichel C.C., Zhu X.R., Bader V., Linnartz B., Schmidt S., Lubbert H. Mono- and double-mutant mouse models of Parkinson's disease display severe mitochondrial damage. Hum. Mol. Genet. (2007) doi 10.1093/hmg/ddm083.

  24. Martin L.J., Pan Y., Price A.C., Sterling W., Copeland N.G., Jenkins N.A., Price D.L., Lee M.K. Parkinson's disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J. Neurosci. (2006) 26:41–50.[Abstract/Free Full Text]

  25. Klivenyi P., Siwek D., Gardian G., Yang L., Starkov A., Cleren C., Ferrante R.J., Kowall N.W., Abeliovich A., Beal M.F. Mice lacking alpha-synuclein are resistant to mitochondrial toxins. Neurobiol. Dis. (2006) 21:541–548.[CrossRef][Web of Science][Medline]

  26. Nieto M., Gil-Bea F.J., Dalfo E., Cuadrado M., Cabodevilla F., Sanchez B., Catena S., Sesma T., Ribe E., Ferrer I., et al. Increased sensitivity to MPTP in human alpha-synuclein A30P transgenic mice. Neurobiol. Aging (2006) 27:848–856.[CrossRef][Web of Science][Medline]

  27. Song D.D., Shults C.W., Sisk A., Rockenstein E., Masliah E. Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP. Exp. Neurol. (2004) 186:158–172.[CrossRef][Web of Science][Medline]

  28. Fan Y., Limprasert P., Murray I.V., Smith A.C., Lee V.M., Trojanowski J.Q., Sopher B.L., La Spada A.R. Beta-synuclein modulates alpha-synuclein neurotoxicity by reducing alpha-synuclein protein expression. Hum. Mol. Genet. (2006) 15:3002–3011.[Abstract/Free Full Text]

  29. Tsigelny I.F., Bar-On P., Sharikov Y., Crews L., Hashimoto M., Miller M.A., Keller S.H., Platoshyn O., Yuan J.X., Masliah E. Dynamics of alpha-synuclein aggregation and inhibition of pore-like oligomer development by beta-synuclein. FEBS J. (2007) 274:1862–1877.[CrossRef][Medline]

  30. Hashimoto M., Bar-On P., Ho G., Takenouchi T., Rockenstein E., Crews L., Masliah E. Beta-synuclein regulates Akt activity in neuronal cells. A possible mechanism for neuroprotection in Parkinson's disease. J. Biol. Chem. (2004) 279:23622–23629.[Abstract/Free Full Text]

  31. Mosharov E.V., Staal R.G., Bove J., Prou D., Hananiya A., Markov D., Poulsen N., Larsen K.E., Moore C.M., Troyer M.D., et al. Alpha-synuclein overexpression increases cytosolic catecholamine concentration. J. Neurosci. (2006) 26:9304–9311.[Abstract/Free Full Text]

  32. Hasegawa T., Matsuzaki-Kobayashi M., Takeda A., Sugeno N., Kikuchi A., Furukawa K., Perry G., Smith M.A., Itoyama Y. Alpha-synuclein facilitates the toxicity of oxidized catechol metabolites: implications for selective neurodegeneration in Parkinson's disease. FEBS Lett. (2006) 580:2147–2152.[CrossRef][Web of Science][Medline]

  33. Klegeris A., Pelech S., Giasson B.I., Maguire J., Zhang H., McGeer E.G., McGeer P.L. alpha-Synuclein activates stress signaling protein kinases in THP-1 cells and microglia. Neurobiol. Aging (2006) doi:10.1016/j.neurobiolaging.2006.11.013.

  34. Winner B., Rockenstein E., Lie D.C., Aigner R., Mante M., Bogdahn U., Couillard-Depres S., Masliah E., Winkler J. Mutant alpha-synuclein exacerbates age-related decrease of neurogenesis. Neurobiol. Aging (2007) doi:10.1016/j.neurobiolaging.2006.12.016.

  35. Lee H.J., Khoshaghideh F., Lee S., Lee S.J. Impairment of microtubule-dependent trafficking by overexpression of alpha-synuclein. Eur. J. Neurosci. (2006) 24:3153–3162.[CrossRef][Web of Science][Medline]

  36. Sung J.Y., Lee H.J., Jeong E.I., Oh Y., Park J., Kang K.S., Chung K.C. alpha-Synuclein overexpression reduces gap junctional intercellular communication in dopaminergic neuroblastoma cells. Neurosci. Lett. (2007) 416:289–293.[CrossRef][Web of Science][Medline]

  37. Kontopoulos E., Parvin J.D., Feany M.B. Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum. Mol. Genet. (2006) 15:3012–3023.[Abstract/Free Full Text]

  38. Zhang Y., Gao J., Chung K.K., Huang H., Dawson V.L., Dawson T.M. Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc. Natl Acad. Sci. USA (2000) 97:13354–13359.[Abstract/Free Full Text]

  39. Shimura H., Hattori N., Kubo S., Mizuno Y., Asakawa S., Minoshima S., Shimizu N., Iwai K., Chiba T., Tanaka K., et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat. Genet. (2000) 25:302–305.[CrossRef][Web of Science][Medline]

  40. Kitada T., Asakawa S., Hattori N., Matsumine H., Yamamura Y., Minoshima S., Yokochi M., Mizuno Y., Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature (1998) 392:605–608.[CrossRef][Medline]

  41. Dawson T.M. Parkin and defective ubiquitination in Parkinson's disease. J. Neural Transm. Suppl. (2006) 70:209–213.[Medline]

  42. Feany M.B., Pallanck L.J. Parkin: a multipurpose neuroprotective agent? Neuron (2003) 38:13–16.[CrossRef][Web of Science][Medline]

  43. Henn I.H., Bouman L., Schlehe J.S., Schlierf A., Schramm J.E., Wegener E., Nakaso K., Culmsee C., Berninger B., Krappmann D., et al. Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor-kappaB signaling. J. Neurosci. (2007) 27:1868–1878.[Abstract/Free Full Text]

  44. Fallon L., Belanger C.M., Corera A.T., Kontogiannea M., Regan-Klapisz E., Moreau F., Voortman J., Haber M., Rouleau G., Thorarinsdottir T., et al. A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling. Nat. Cell Biol. (2006) 8:834–842.[CrossRef][Web of Science][Medline]

  45. Riparbelli M.G., Callaini G. The Drosophila parkin homologue is required for normal mitochondrial dynamics during spermiogenesis. Dev. Biol. (2007) 303:108–120.[CrossRef][Web of Science][Medline]

  46. Kuroda Y., Mitsui T., Kunishige M., Shono M., Akaike M., Azuma H., Matsumoto T. Parkin enhances mitochondrial biogenesis in proliferating cells. Hum. Mol. Genet. (2006) 15:883–895.[Abstract/Free Full Text]

  47. Yang Y., Gehrke S., Imai Y., Huang Z., Ouyang Y., Wang J.W., Yang L., Beal M.F., Vogel H., Lu B. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc. Natl Acad. Sci. USA (2006) 103:10793–10798.[Abstract/Free Full Text]

  48. Clark I.E., Dodson M.W., Jiang C., Cao J.H., Huh J.R., Seol J.H., Yoo S.J., Hay B.A., Guo M. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature (2006) 441:1162–1166.[CrossRef][Medline]

  49. Park J., Lee S.B., Lee S., Kim Y., Song S., Kim S., Bae E., Kim J., Shong M., Kim J.M., et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature (2006) 441:1157–1161.[CrossRef][Medline]

  50. Casarejos M.J., Menendez J., Solano R.M., Rodriguez-Navarro J.A., Garcia de Yebenes J., Mena M.A. Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced by minocycline. J. Neurochem. (2006) 97:934–946.[CrossRef][Web of Science][Medline]

  51. LaVoie M.J., Ostaszewski B.L., Weihofen A., Schlossmacher M.G., Selkoe D.J. Dopamine covalently modifies and functionally inactivates parkin. Nat. Med. (2005) 11:1214–1221.[CrossRef][Web of Science][Medline]

  52. Chung K.K., Thomas B., Li X., Pletnikova O., Troncoso J.C., Marsh L., Dawson V.L., Dawson T.M. S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science (2004) 304:1328–1331.[Abstract/Free Full Text]

  53. Smith P.D., Crocker S.J., Jackson-Lewis V., Jordan-Sciutto K.L., Hayley S., Mount M.P., O'Hare M.J., Callaghan S., Slack R.S., Przedborski S., et al. Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease. Proc. Natl Acad. Sci. USA (2003) 100:13650–13655.[Abstract/Free Full Text]

  54. Avraham E., Rott R., Liani E., Szargel R., Engelender S. Phosphorylation of parkin by the cyclin-dependent kinase 5 at the linker region modulates its ubiquitin-ligase activity and aggregation. J. Biol. Chem. (2007) 282:12842–12850.[Abstract/Free Full Text]

  55. Wang C., Ko H.S., Thomas B., Tsang F., Chew K.C., Tay S.P., Ho M.W., Lim T.M., Soong T.W., Pletnikova O., et al. Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function. Hum. Mol. Genet. (2005) 14:3885–3897.[Abstract/Free Full Text]

  56. Wong E.S., Tan J.M., Wang C., Zhang Z., Tay S.P., Zaiden N., Ko H.S., Dawson V.L., Dawson T.M., Lim K.L. Relative sensitivity of parkin and other cysteine-containing enzymes to stress-induced solubility alterations. J. Biol. Chem. (2007) 282:12310–12318.[Abstract/Free Full Text]

  57. Sang T.K., Chang H.Y., Lawless G.M., Ratnaparkhi A., Mee L., Ackerson L.C., Maidment N.T., Krantz D.E., Jackson G.R. A Drosophila model of mutant human parkin-induced toxicity demonstrates selective loss of dopaminergic neurons and dependence on cellular dopamine. J. Neurosci. (2007) 27:981–992.[Abstract/Free Full Text]

  58. Moore D.J., West A.B., Dawson V.L., Dawson T.M. Molecular pathophysiology of Parkinson's disease. Annu. Rev. Neurosci. (2005) 28:57–87.[CrossRef][Web of Science][Medline]

  59. Thomas B., von Coelln R., Mandir A.S., Trinkaus D.B., Farah M.H., Leong Lim K., Calingasan N.Y., Flint Beal M., Dawson V.L., Dawson T.M. MPTP and DSP-4 susceptibility of substantia nigra and locus coeruleus catecholaminergic neurons in mice is independent of parkin activity. Neurobiol. Dis. (2007) 26:312–322.[CrossRef][Web of Science][Medline]

  60. Perez F.A., Curtis W.R., Palmiter R.D. Parkin-deficient mice are not more sensitive to 6-hydroxydopamine or methamphetamine neurotoxicity. BMC Neurosci. (2005) 6:71.[CrossRef][Medline]

  61. von Coelln R., Thomas B., Andrabi S.A., Lim K.L., Savitt J.M., Saffary R., Stirling W., Bruno K., Hess E.J., Lee M.K., et al. Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy. J. Neurosci. (2006) 26:3685–3696.[Abstract/Free Full Text]

  62. Solano R.M., Menendez J., Casarejos M.J., Rodriguez-Navarro J.A., Garcia de Yebenes J., Mena M.A. Midbrain neuronal cultures from parkin mutant mice are resistant to nitric oxide-induced toxicity. Neuropharmacology (2006) 51:327–340.[CrossRef][Web of Science][Medline]

  63. Bonifati V., Rizzu P., van Baren M.J., Schaap O., Breedveld G.J., Krieger E., Dekker M.C., Squitieri F., Ibanez P., Joosse M., et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science (2003) 299:256–259.[Abstract/Free Full Text]

  64. Hedrich K., Djarmati A., Schafer N., Hering R., Wellenbrock C., Weiss P.H., Hilker R., Vieregge P., Ozelius L.J., Heutink P., et al. DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease. Neurology (2004) 62:389–394.[Abstract/Free Full Text]

  65. Bandopadhyay R., Kingsbury A.E., Cookson M.R., Reid A.R., Evans I.M., Hope A.D., Pittman A.M., Lashley T., Canet-Aviles R., Miller D.W., et al. The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease. Brain (2004) 127:420–430.[Abstract/Free Full Text]

  66. Zhang L., Shimoji M., Thomas B., Moore D.J., Yu S.W., Marupudi N.I., Torp R., Torgner I.A., Ottersen O.P., Dawson T.M., et al. Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis. Hum. Mol. Genet. (2005) 14:2063–2073.[Abstract/Free Full Text]

  67. Canet-Aviles R.M., Wilson M.A., Miller D.W., Ahmad R., McLendon C., Bandyopadhyay S., Baptista M.J., Ringe D., Petsko G.A., Cookson M.R. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc. Natl Acad. Sci. USA (2004) 101:9103–9108.[Abstract/Free Full Text]

  68. Taira T., Saito Y., Niki T., Iguchi-Ariga S.M., Takahashi K., Ariga H. DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep. (2004) 5:213–218.[CrossRef][Web of Science][Medline]

  69. Paterna J.C., Leng A., Weber E., Feldon J., Bueler H. DJ-1 and Parkin modulate dopamine-dependent behavior and inhibit MPTP-induced nigral dopamine neuron loss in mice. Mol. Ther. (2007) 15:698–704.[Web of Science][Medline]

  70. Inden M., Taira T., Kitamura Y., Yanagida T., Tsuchiya D., Takata K., Yanagisawa D., Nishimura K., Taniguchi T., Kiso Y., et al. PARK7 DJ-1 protects against degeneration of nigral dopaminergic neurons in Parkinson's disease rat model. Neurobiol. Dis. (2006) 24:144–158.[CrossRef][Web of Science][Medline]

  71. Clements C.M., McNally R.S., Conti B.J., Mak T.W., Ting J.P. DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc. Natl Acad. Sci. USA (2006) 103:15091–15096.[Abstract/Free Full Text]

  72. Zhou W., Freed C.R. DJ-1 up-regulates glutathione synthesis during oxidative stress and inhibits A53T alpha-synuclein toxicity. J. Biol. Chem. (2005) 280:43150–43158.[Abstract/Free Full Text]

  73. Shendelman S., Jonason A., Martinat C., Leete T., Abeliovich A. DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol. (2004) 2:e362.[CrossRef][Medline]

  74. Zhou W., Zhu M., Wilson M.A., Petsko G.A., Fink A.L. The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein. J. Mol. Biol. (2006) 356:1036–1048.[CrossRef][Web of Science][Medline]

  75. Moore D.J., Zhang L., Troncoso J., Lee M.K., Hattori N., Mizuno Y., Dawson T.M., Dawson V.L. Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Hum. Mol. Genet. (2005) 14:71–84.[Abstract/Free Full Text]

  76. Gorner K., Holtorf E., Waak J., Pham T.T., Vogt-Weisenhorn D.M., Wurst W., Haass C., Kahle P.J. Structural determinants of the C-terminal helix-kink-helix motif essential for protein stability and survival promoting activity of DJ-1. J. Biol. Chem. (2007) 282:13680–13691.[Abstract/Free Full Text]

  77. Hulleman J.D., Mirzaei H., Guigard E., Taylor K.L., Ray S.S., Kay C.M., Regnier F.E., Rochet J.C. Destabilization of DJ-1 by familial substitution and oxidative modifications: implications for Parkinson's disease. Biochemistry (2007) 46:5776–5789.[CrossRef][Medline]

  78. Ooe H., Maita C., Maita H., Iguchi-Ariga S.M., Ariga H. Specific cleavage of DJ-1 under an oxidative condition. Neurosci. Lett. (2006) 406:165–168.[CrossRef][Web of Science][Medline]

  79. Choi J., Sullards M.C., Olzmann J.A., Rees H.D., Weintraub S.T., Bostwick D.E., Gearing M., Levey A.I., Chin L.S., Li L. Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases. J. Biol. Chem. (2006) 281:10816–10824.[Abstract/Free Full Text]

  80. Goldberg M.S., Pisani A., Haburcak M., Vortherms T.A., Kitada T., Costa C., Tong Y., Martella G., Tscherter A., Martins A., et al. Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron (2005) 45:489–496.[CrossRef][Web of Science][Medline]

  81. Chen L., Cagniard B., Mathews T., Jones S., Koh H.C., Ding Y., Carvey P.M., Ling Z., Kang U.J., Zhuang X. Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. J. Biol. Chem. (2005) 280:21418–21426.[Abstract/Free Full Text]

  82. Kim R.H., Smith P.D., Aleyasin H., Hayley S., Mount M.P., Pownall S., Wakeham A., You-Ten A.J., Kalia S.K., Horne P., et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc. Natl Acad. Sci. USA (2005) 102:5215–5220.[Abstract/Free Full Text]

  83. Bretaud S., Allen C., Ingham P.W., Bandmann O. p53-dependent neuronal cell death in a DJ-1-deficient zebrafish model of Parkinson's disease. J. Neurochem. (2007) 100:1626–1635.[Web of Science][Medline]

  84. Pisani A., Martella G., Tscherter A., Costa C., Mercuri N.B., Bernardi G., Shen J., Calabresi P. Enhanced sensitivity of DJ-1-deficient dopaminergic neurons to energy metabolism impairment: role of Na+/K+ ATPase. Neurobiol. Dis. (2006) 23:54–60.[CrossRef][Web of Science][Medline]

  85. Yang Y., Gehrke S., Haque M.E., Imai Y., Kosek J., Yang L., Beal M.F., Nishimura I., Wakamatsu K., Ito S., et al. Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling. Proc. Natl Acad. Sci. USA (2005) 102:13670–13675.[Abstract/Free Full Text]

  86. Junn E., Taniguchi H., Jeong B.S., Zhao X., Ichijo H., Mouradian M.M. Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. Proc. Natl Acad. Sci. USA (2005) 102:9691–9696.[Abstract/Free Full Text]

  87. Zhong N., Kim C.Y., Rizzu P., Geula C., Porter D.R., Pothos E.N., Squitieri F., Heutink P., Xu J. DJ-1 transcriptionally up-regulates the human tyrosine hydroxylase by inhibiting the sumoylation of pyrimidine tract-binding protein-associated splicing factor. J. Biol. Chem. (2006) 281:20940–20948.[Abstract/Free Full Text]

  88. Valente E.M., Abou-Sleiman P.M., Caputo V., Muqit M.M., Harvey K., Gispert S., Ali Z., Del Turco D., Bentivoglio A.R., Healy D.G., et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science (2004) 304:1158–1160.[Abstract/Free Full Text]

  89. Klein C., Grunewald A., Hedrich K. Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology (2006) 66:1129–1130. author reply 1129–1130.[Free Full Text]

  90. Gandhi S., Muqit M.M., Stanyer L., Healy D.G., Abou-Sleiman P.M., Hargreaves I., Heales S., Ganguly M., Parsons L., Lees A.J., et al. PINK1 protein in normal human brain and Parkinson's disease. Brain (2006) 129:1720–1731.[Abstract/Free Full Text]

  91. Leutenegger A.L., Salih M.A., Ibanez P., Mukhtar M.M., Lesage S., Arabi A., Lohmann E., Durr A., Ahmed A.E., Brice A. Juvenile-onset Parkinsonism as a result of the first mutation in the adenosine triphosphate orientation domain of PINK1. Arch. Neurol. (2006) 63:1257–1261.[Abstract/Free Full Text]

  92. Beilina A., Van Der Brug M., Ahmad R., Kesavapany S., Miller D.W., Petsko G.A., Cookson M.R. Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc. Natl Acad. Sci. USA (2005) 102:5703–5708.[Abstract/Free Full Text]

  93. Silvestri L., Caputo V., Bellacchio E., Atorino L., Dallapiccola B., Valente E.M., Casari G. Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum. Mol. Genet. (2005) 14:3477–3492.[Abstract/Free Full Text]

  94. Sim C.H., Lio D.S., Mok S.S., Masters C.L., Hill A.F., Culvenor J.G., Cheng H.C. C-terminal truncation and Parkinson's disease-associated mutations down-regulate the protein serine/threonine kinase activity of PTEN-induced kinase-1. Hum. Mol. Genet. (2006) 15:3251–3262.[Abstract/Free Full Text]

  95. Scheele C., Petrovic N., Faghihi M.A., Lassmann T., Fredriksson K., Rooyackers O., Wahlestedt C., Good L., Timmons J.A. The human PINK1 locus is regulated in vivo by a non-coding natural antisense RNA during modulation of mitochondrial function. BMC Genom. (2007) 8:74.[CrossRef]

  96. Petit A., Kawarai T., Paitel E., Sanjo N., Maj M., Scheid M., Chen F., Gu Y., Hasegawa H., Salehi-Rad S., et al. Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J. Biol. Chem. (2005) 280:34025–34032.[Abstract/Free Full Text]

  97. Deng H., Jankovic J., Guo Y., Xie W., Le W. Small interfering RNA targeting the PINK1 induces apoptosis in dopaminergic cells SH-SY5Y. Biochem. Biophys. Res. Commun. (2005) 337:1133–1138.[Web of Science][Medline]

  98. Tang B., Xiong H., Sun P., Zhang Y., Wang D., Hu Z., Zhu Z., Ma H., Pan Q., Xia J.H., et al. Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease. Hum. Mol. Genet. (2006) 15:1816–1825.[Abstract/Free Full Text]

  99. Muqit M.M., Abou-Sleiman P.M., Saurin A.T., Harvey K., Gandhi S., Deas E., Eaton S., Payne Smith M.D., Venner K., Matilla A., et al. Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress. J. Neurochem. (2006) 98:156–169.[CrossRef][Web of Science][Medline]

  100. Murakami T., Moriwaki Y., Kawarabayashi T., Nagai M., Ohta Y., Deguchi K., Kurata T., Takehisa Y., Matsubara E., Ikeda M., et al. PINK1, a gene product of PARK6, accumulates in {alpha}-synucleinopathy brains. J. Neurol. Neurosurg. Psychiatry (2007) 78:653–654.[Free Full Text]

  101. Hoepken H.H., Gispert S., Morales B., Wingerter O., Del Turco D., Mulsch A., Nussbaum R.L., Muller K., Drose S., Brandt U., et al. Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. Neurobiol. Dis. (2007) 25:401–411.[CrossRef][Web of Science][Medline]

  102. Wang D., Qian L., Xiong H., Liu J., Neckameyer W.S., Oldham S., Xia K., Wang J., Bodmer R., Zhang Z. Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila. Proc. Natl Acad. Sci. USA (2006) 103:13520–13525.[Abstract/Free Full Text]

  103. Zimprich A., Biskup S., Leitner P., Lichtner P., Farrer M., Lincoln S., Kachergus J., Hulihan M., Uitti R.J., Calne D.B., et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron (2004) 44:601–607.[CrossRef][Web of Science][Medline]

  104. Paisan-Ruiz C., Jain S., Evans E.W., Gilks W.P., Simon J., van der Brug M., Lopez de Munain A., Aparicio S., Gil A.M., Khan N., et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron (2004) 44:595–600.[CrossRef][Web of Science][Medline]

  105. Hardy J., Cai H., Cookson M.R., Gwinn-Hardy K., Singleton A. Genetics of Parkinson's disease and parkinsonism. Ann. Neurol. (2006) 60:389–398.[CrossRef][Web of Science][Medline]

  106. Biskup S., Moore D.J., Celsi F., Higashi S., West A.B., Andrabi S.A., Kurkinen K., Yu S.W., Savitt J.M., Waldvogel H.J., et al. Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann. Neurol. (2006) 60:557–569.[CrossRef][Web of Science][Medline]

  107. Higashi S., Moore D.J., Colebrooke R.E., Biskup S., Dawson V.L., Arai H., Dawson T.M., Emson P.C. Expression and localization of Parkinson's disease-associated leucine-rich repeat kinase 2 in the mouse brain. J. Neurochem. (2007) 100:368–381.[CrossRef][Web of Science][Medline]

  108. Galter D., Westerlund M., Carmine A., Lindqvist E., Sydow O., Olson L. LRRK2 expression linked to dopamine-innervated areas. Ann. Neurol. (2006) 59:714–719.[CrossRef][Web of Science][Medline]

  109. Taymans J.M., Van den Haute C., Baekelandt V. Distribution of PINK1 and LRRK2 in rat and mouse brain. J. Neurochem. (2006) 98:951–961.[CrossRef][Web of Science][Medline]

  110. Simon-Sanchez J., Herranz-Perez V., Olucha-Bordonau F., Perez-Tur J. LRRK2 is expressed in areas affected by Parkinson's disease in the adult mouse brain. Eur. J. Neurosci. (2006) 23:659–666.[CrossRef][Web of Science][Medline]

  111. Sakaguchi-Nakashima A., Meir J.Y., Jin Y., Matsumoto K., Hisamoto N. LRK-1, a C. elegans PARK8-related kinase, regulates axonal-dendritic polarity of SV proteins. Curr. Biol. (2007) 17:592–598.[CrossRef][Web of Science][Medline]

  112. Hatano T., Kubo S., Imai S., Maeda M., Ishikawa K., Mizuno Y., Hattori N. Leucine-rich repeat kinase 2 associates with lipid rafts. Hum. Mol. Genet. (2007) 16:678–690.[Abstract/Free Full Text]

  113. Zhu X., Siedlak S.L., Smith M.A., Perry G., Chen S.G. LRRK2 protein is a component of Lewy bodies. Ann. Neurol. (2006) 60:617–618. author reply 618–619.[Web of Science][Medline]

  114. MacLeod D., Dowman J., Hammond R., Leete T., Inoue K., Abeliovich A. The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron (2006) 52:587–593.[CrossRef][Web of Science][Medline]

  115. Li C., Beal M.F. Leucine-rich repeat kinase 2: a new player with a familiar theme for Parkinson's disease pathogenesis. Proc. Natl Acad. Sci. USA (2005) 102:16535–16536.[Free Full Text]

  116. Deng H., Le W., Guo Y., Hunter C.B., Xie W., Huang M., Jankovic J. Genetic analysis of LRRK2 mutations in patients with Parkinson disease. J. Neurol. Sci. (2006) 251:102–106.[CrossRef][Web of Science][Medline]

  117. West A.B., Moore D.J., Biskup S., Bugayenko A., Smith W.W., Ross C.A., Dawson V.L., Dawson T.M. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl Acad. Sci. USA (2005) 102:16842–16847.[Abstract/Free Full Text]

  118. Gloeckner C.J., Kinkl N., Schumacher A., Braun R.J., O'Neill E., Meitinger T., Kolch W., Prokisch H., Ueffing M. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum. Mol. Genet. (2006) 15:223–232.[Abstract/Free Full Text]

  119. Greggio E., Jain S., Kingsbury A., Bandopadhyay R., Lewis P., Kaganovich A., van der Brug M.P., Beilina A., Blackinton J., Thomas K.J., et al. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol. Dis. (2006) 23:329–341.[Web of Science][Medline]

  120. Smith W.W., Pei Z., Jiang H., Dawson V.L., Dawson T.M., Ross C.A. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat. Neurosci. (2006) 9:1231–1233.[CrossRef][Web of Science][Medline]

  121. West A.B., Moore D.J., Choi C., Andrabi S.A., Li X., Dikeman D., Biskup S., Zhang Z., Lim K.L., Dawson V.L., et al. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum. Mol. Genet. (2007) 16:223–232.[Abstract/Free Full Text]

  122. Ito G., Okai T., Fujino G., Takeda K., Ichijo H., Katada T., Iwatsubo T. GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. Biochemistry (2007) 46:1380–1388.[CrossRef][Medline]

  123. Greggio E., Lewis P.A., van der Brug M.P., Ahmad R., Kaganovich A., Ding J., Beilina A., Baker A.K., Cookson M.R. Mutations in LRRK2/dardarin associated with Parkinson disease are more toxic than equivalent mutations in the homologous kinase LRRK1. J. Neurochem. (2007) doi:10.1111/j.1471-4159.2007.04523.x.

  124. Lewis P.A., Greggio E., Beilina A., Jain S., Baker A., Cookson M.R. The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochem. Biophys. Res. Commun. (2007) 357:668–671.[CrossRef][Web of Science][Medline]

  125. Smith W.W., Pei Z., Jiang H., Moore D.J., Liang Y., West A.B., Dawson V.L., Dawson T.M., Ross C.A. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc. Natl Acad. Sci. USA (2005) 102:18676–18681.[Abstract/Free Full Text]

  126. Iaccarino C., Crosio C., Vitale C., Sanna G., Carri M.T., Barone P. Apoptotic mechanisms in mutant LRRK2-mediated cell death. Hum. Mol. Genet. (2007) 16:1319–1326.[Abstract/Free Full Text]

  127. White L.R., Toft M., Kvam S.N., Farrer M.J., Aasly J.O. MAPK-pathway activity, Lrrk2 G2019S, and Parkinson's disease. J. Neurosci. Res. (2007) 85:1288–1294.[CrossRef][Web of Science][Medline]

  128. Keeney P.M., Xie J., Capaldi R.A., Bennett J.P. Jr. Parkinson's disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J. Neurosci. (2006) 26:5256–5264.[Abstract/Free Full Text]

  129. Beal M.F. Mitochondria take center stage in aging and neurodegeneration. Ann. Neurol. (2005) 58:495–505.[CrossRef][Web of Science][Medline]

  130. Swerdlow R.H., Parks J.K., Miller S.W., Tuttle J.B., Trimmer P.A., Sheehan J.P., Bennett J.P. Jr, Davis R.E., Parker W.D. Jr. Origin and functional consequences of the complex I defect in Parkinson's disease. Ann. Neurol. (1996) 40:663–671.[CrossRef][Web of Science][Medline]

  131. Gorell J.M., Johnson C.C., Rybicki B.A., Peterson E.L., Richardson R.J. The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living. Neurology (1998) 50:1346–1350.[Abstract/Free Full Text]

  132. Langston J.W., Ballard P., Tetrud J.W., Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science (1983) 219:979–980.[Abstract/Free Full Text]

  133. Betarbet R., Sherer T.B., MacKenzie G., Garcia-Osuna M., Panov A.V., Greenamyre J.T. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. (2000) 3:1301–1306.[CrossRef][Web of Science][Medline]

  134. Thiruchelvam M., Richfield E.K., Baggs R.B., Tank A.W., Cory-Slechta D.A. The nigrostriatal dopaminergic system as a preferential target of repeated exposures to combined paraquat and maneb: implications for Parkinson's disease. J. Neurosci. (2000) 20:9207–9214.[Abstract/Free Full Text]

  135. Lin M.T., Beal M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature (2006) 443:787–795.[CrossRef][Medline]

  136. Bender A., Krishnan K.J., Morris C.M., Taylor G.A., Reeve A.K., Perry R.H., Jaros E., Hersheson J.S., Betts J., Klopstock T., et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat. Genet. (2006) 38:515–517.[CrossRef][Web of Science][Medline]

  137. Kraytsberg Y., Kudryavtseva E., McKee A.C., Geula C., Kowall N.W., Khrapko K. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat. Genet. (2006) 38:518–520.[CrossRef][Web of Science][Medline]

  138. Ekstrand M.I., Terzioglu M., Galter D., Zhu S., Hofstetter C., Lindqvist E., Thams S., Bergstrand A., Hansson F.S., Trifunovic A., et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc. Natl Acad. Sci. USA (2007) 104:1325–1330.[Abstract/Free Full Text]

  139. Liang C.L., Wang T.T., Luby-Phelps K., German D.C. Mitochondria mass is low in mouse substantia nigra dopamine neurons: implications for Parkinson's disease. Exp. Neurol. (2007) 203:370–380.[CrossRef][Web of Science][Medline]

  140. Dexter D.T., Sian J., Rose S., Hindmarsh J.G., Mann V.M., Cooper J.M., Wells F.R., Daniel S.E., Lees A.J., Schapira A.H., et al. Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease. Ann. Neurol. (1994) 35:38–44.[CrossRef][Web of Science][Medline]

  141. Chinta S.J., Andersen J.K. Reversible inhibition of mitochondrial complex I activity following chronic dopaminergic glutathione depletion in vitro: implications for Parkinson's disease. Free Radic. Biol. Med. (2006) 41:1442–1448.[CrossRef][Web of Science][Medline]

  142. St-Pierre J., Drori S., Uldry M., Silvaggi J.M., Rhee J., Jager S., Handschin C., Zheng K., Lin J., Yang W., et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell (2006) 127:397–408.[CrossRef][Web of Science][Medline]

  143. McGill J.K., Beal M.F. PGC-1alpha, a new therapeutic target in Huntington's disease? Cell (2006) 127:465–468.[CrossRef][Web of Science][Medline]

  144. Ramsey C.P., Glass C.A., Montgomery M.B., Lindl K.A., Ritson G.P., Chia L.A., Hamilton R.L., Chu C.T., Jordan-Sciutto K.L. Expression of Nrf2 in neurodegenerative diseases. J. Neuropathol. Exp. Neurol. (2007) 66:75–85.[Web of Science][Medline]

  145. Lee J.M., Johnson J.A. An important role of Nrf2-ARE pathway in the cellular defense mechanism. J. Biochem. Mol. Biol. (2004) 37:139–143.[Web of Science][Medline]

  146. Kobayashi A., Kang M.I., Watai Y., Tong K.I., Shibata T., Uchida K., Yamamoto M. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol. Cell. Biol. (2006) 26:221–229.[Abstract/Free Full Text]

  147. Itoh K., Wakabayashi N., Katoh Y., Ishii T., Igarashi K., Engel J.D., Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. (1999) 13:76–86.[Abstract/Free Full Text]

  148. Dinkova-Kostova A.T., Liby K.T., Stephenson K.K., Holtzclaw W.D., Gao X., Suh N., Williams C., Risingsong R., Honda T., Gribble G.W., et al. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc. Natl Acad. Sci. USA (2005) 102:4584–4589.[Abstract/Free Full Text]

  149. Burton N.C., Kensler T.W., Guilarte T.R. In vivo modulation of the Parkinsonian phenotype by Nrf2. Neurotoxicology (2006) 27:1094–1100.[CrossRef][Medline]

  150. Shih A.Y., Imbeault S., Barakauskas V., Erb H., Jiang L., Li P., Murphy T.H. Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J. Biol. Chem. (2005) 280:22925–22936.[Abstract/Free Full Text]

  151. Calkins M.J., Jakel R.J., Johnson D.A., Chan K., Kan Y.W., Johnson J.A. Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc. Natl Acad. Sci. USA (2005) 102:244–249.[Abstract/Free Full Text]

  152. Liberatore G.T., Jackson-Lewis V., Vukosavic S., Mandir A.S., Vila M., McAuliffe W.G., Dawson V.L., Dawson T.M., Przedborski S. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat. Med. (1999) 5:1403–1409.[CrossRef][Web of Science][Medline]

  153. Teismann P., Tieu K., Choi D.K., Wu D.C., Naini A., Hunot S., Vila M., Jackson-Lewis V., Przedborski S. Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration. Proc. Natl Acad. Sci. USA (2003) 100:5473–5478.[Abstract/Free Full Text]

  154. Ries V., Henchcliffe C., Kareva T., Rzhetskaya M., Bland R., During M.J., Kholodilov N., Burke R.E. Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease. Proc. Natl Acad. Sci. USA (2006) 103:18757–18762.[Abstract/Free Full Text]

  155. Pesah Y., Pham T., Burgess H., Middlebrooks B., Verstreken P., Zhou Y., Harding M., Bellen H., Mardon G. Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development (2004) 131:2183–2194.[Abstract/Free Full Text]

  156. Palacino J.J., Sagi D., Goldberg M.S., Krauss S., Motz C., Wacker M., Klose J., Shen J. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J. Biol. Chem. (2004) 279:18614–18622.[Abstract/Free Full Text]

  157. Darios F., Corti O., Lucking C.B., Hampe C., Muriel M.P., Abbas N., Gu W.J., Hirsch E.C., Rooney T., Ruberg M., et al. Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death. Hum. Mol. Genet. (2003) 12:517–526.[Abstract/Free Full Text]

  158. Meulener M.C., Xu K., Thomson L., Ischiropoulos H., Bonini N.M. Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging. Proc. Natl Acad. Sci. USA (2006) 103:12517–12522.[Abstract/Free Full Text]


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