Human Molecular Genetics

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Human Molecular Genetics, 2002, Vol. 11, No. 20 2395-2407
© 2002 Oxford University Press

Impaired dopamine storage resulting from -synuclein mutations may contribute to the pathogenesis of Parkinson's disease

Julie Lotharius^* and Patrik Brundin

Section for Neuronal Survival, Wallenberg Neuroscience Center, Lund University, Lund, Sweden

Received July 8, 2002; Accepted August 5, 2002

	ABSTRACT

TOP ABSTRACT EVIDENCE OF OXIDATIVE STRESS... IS CYTOSOLIC DOPAMINE TOXIC? MUTATIONS IN THE {alpha}... POTENTIAL ROLE OF {alpha}... SYNAPTIC VESICLE RECYCLING: AN... REGULATION OF PLD2 ACTIVITY... FATTY ACID-BINDING PROPERTIES OF... ROLE OF {alpha}-SYNUCLEIN IN... CONCLUDING REMARKS REFERENCES

 
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the inability to initiate, execute and control movement. Neuropathologically, there is a striking loss of dopamine-producing neurons in the substantia nigra pars compacta, accompanied by depletion of dopamine in the striatum. Most forms of PD are sporadic, though in some cases familial inheritance is observed. In the late 1990s, two mutations in the -synuclein gene were linked to rare, autosomal dominant forms of PD. Previously cloned from cholinergic vesicles of the Torpedo electric ray, -synuclein is highly enriched in presynaptic nerve terminals and appears to be involved in synapse maintenance and plasticity. It is expressed ubiquitously in the brain, raising the important question of why dopaminergic neurons are primarily targeted in persons carrying mutations in -synuclein. In this article, we review the current literature on -synuclein and suggest a possible role for this protein in vesicle recycling via its regulation of phospholipase D2, its fatty acid-binding properties, or both. Exogenous application of dopamine, as well as redistribution of vesicular dopamine to the cytoplasm, can be toxic to dopaminergic neurons. Thus, impaired neurotransmitter storage arising from mutations in -synuclein could lead to cytoplasmic accumulation of dopamine. The breakdown of this labile neurotransmitter in the cytoplasm could, in turn, promote oxidative stress and metabolic dysfunction, both of which have been observed in nigral tissue from PD patients.

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting 1.8% of people over the age of 65 years (1). Patients display tremor at rest, postural instability, slowness of movement, and rigidity, symptoms that are initially responsive to treatment with the dopamine precursor L-DOPA. Over 60% of pigmented neurons in the substantia nigra pars compacta (SNpc) are lost in PD (2–4), which results in a >90% reduction in dopamine in the striatum (5). PD is also characterized by Lewy bodies, cytoplasmic inclusions that are composed predominantly of fibrillar -synuclein (6,7). Even though nigral dopaminergic neurons are the most vulnerable cell type in PD, neurodegeneration and Lewy bodies are found in other brain regions (8). This review identifies a potential pathogenic mechanism that could explain why catecholaminergic cells are the prime targets in PD. Based on evidence of increased oxidative stress (OS) in PD, we propose a possible link between a novel gene associated with familial PD, impaired neurotransmitter storage, and enhanced dopamine-dependent OS.

	EVIDENCE OF OXIDATIVE STRESS IN PARKINSON'S DISEASE

TOP ABSTRACT EVIDENCE OF OXIDATIVE STRESS... IS CYTOSOLIC DOPAMINE TOXIC? MUTATIONS IN THE {alpha}... POTENTIAL ROLE OF {alpha}... SYNAPTIC VESICLE RECYCLING: AN... REGULATION OF PLD2 ACTIVITY... FATTY ACID-BINDING PROPERTIES OF... ROLE OF {alpha}-SYNUCLEIN IN... CONCLUDING REMARKS REFERENCES

 
OS is a state of imbalance between the production of reactive oxygen species (ROS) and the capacity of a cell to scavenge these toxic metabolites via its own antioxidant defense machinery. Severe OS can cause cell damage and death by a variety of mechanisms (9). Nigral dopaminergic neurons are particularly prone to OS because the metabolism of dopamine gives rise to various toxic species (10–12). Due to its unstable catechol ring, dopamine can undergo spontaneous oxidation in the presence of molecular oxygen to yield hydrogen peroxide, superoxide and dopamine-o-quinone (11). Alternatively, it can be enzymatically deaminated by monoamine oxidase (MAO) to produce dihydroxyphenylacetic acid (DOPAC) and hydrogen peroxide, which can, in turn, be converted to hydroxyl radicals in the presence of iron (12). Immediately after synthesis, dopamine is taken up into synaptic vesicles by the vesicular monoamine transporter 2 (VMAT2). By virtue of their low pH and MAO-free environment, synaptic storage sites hinder dopamine breakdown. In the cytoplasm, however, dopamine is highly prone to spontaneous and enzymatic degradation. In addition to the detrimental effects of ROS on cellular macromolecules, dopamine and several of its metabolites can also inhibit complex I of the electron-transport chain (13–15), an enzyme essential for cellular ATP synthesis. Incidentally, complex I activity is significantly reduced in nigral tissue from PD patients (16).

Indeed, postmortem studies support the involvement of OS in PD (17,18). For example, the concentration of iron, which catalyzes the formation of hydroxyl radicals from hydrogen peroxide, is much higher in the SN of PD patients than in age-matched controls (19,20). Elevations in manganese superoxide dismutase (21), a neuroprotective enzyme that scavenges mitochondrial superoxide radicals, and reductions in hydrogen peroxide-eliminating systems (22) have also been reported. In addition, oxidative damage to lipids (23), proteins (24,25) and DNA (26) has been detected in diseased nigral tissue. Salsolinol, an endogenous dopamine-derived neurotoxin, is elevated in the cerebrospinal fluid of newly diagnosed PD patients (27). As the disease progresses, residual nigral neurons display increased dopamine turnover that may further enhance OS (28). Additional evidence that dopamine neurons may be particularly sensitive to OS is provided by studies showing that vitamin E deficiency leads to a loss of striatal dopaminergic terminals (29).

	IS CYTOSOLIC DOPAMINE TOXIC?

TOP ABSTRACT EVIDENCE OF OXIDATIVE STRESS... IS CYTOSOLIC DOPAMINE TOXIC? MUTATIONS IN THE {alpha}... POTENTIAL ROLE OF {alpha}... SYNAPTIC VESICLE RECYCLING: AN... REGULATION OF PLD2 ACTIVITY... FATTY ACID-BINDING PROPERTIES OF... ROLE OF {alpha}-SYNUCLEIN IN... CONCLUDING REMARKS REFERENCES

 
A role for cytosolic dopamine in nigral degeneration was first supported by studies using the psychostimulant D-amphetamine (AMPH) and its derivatives, for example methamphetamine (METH). These psychotropic drugs are taken up into dopaminergic terminals by the plasma membrane dopamine transporter (DAT), where their weak base action dissipates the proton gradient across vesicular membranes (30). Disruption of this gradient, which provides the driving force for dopamine uptake into vesicles, leads to an accumulation of dopamine in the cytoplasm (31). This, in turn, promotes the outward transport of dopamine through the DAT, which underlies the psychostimulant properties of these drugs (31–33). Even though cytoplasmic dopamine is quickly extruded from the cell by the DAT, transient accumulation of this neurotransmitter in the cytosol can lead to the formation of ROS (34,35). Cells treated with either AMPH or METH exhibit oxidative protein modifications (35,36), vacuolation of intracellular organelles (34), neurite degeneration (34,37) and in some cases neuronal death (38). Interestingly, AMPH-induced ROS formation and protein carbonylation can be blocked by depleting cells of intracellular dopamine prior to drug exposure (35). METH-induced toxicity in vivo can also be blocked by dopamine depletion, overexpression of copper/zinc superoxide dismutase (Cu/Zn SOD) and antioxidant administration (39–42). In conclusion, these studies provide convincing evidence that physchostimulant-induced toxicity is mediated by dopamine-dependent OS.

Interestingly, dopaminergic cell death mediated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that produces parkinsonism in humans and experimental animals, may also result from aberrant dopamine handling. The active metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP⁺), is a selective complex I inhibitor that can block mitochondrial ATP production (43–45). In addition to its effect on mitochondria, MPP⁺ can be taken up into dopaminergic vesicles by VMAT2 redistributing vesicular dopamine to the cytoplasm (46–49). This, in turn, results in ROS formation and cell death, effects that can be blocked or partially attenuated by depleting cells of intracellular dopamine (50). In conclusion studies using AMPH, METH and MPP⁺ suggest that abnormal accumulation of cytoplasmic DA may play an important role in the pathogenesis of PD by inducing dopamine-dependent OS (Fig. 1).

View larger version (87K): [in this window] [in a new window]   Figure 1. Schematic view of a dopaminergic nigrostriatal terminal depicting the pathways for dopamine (DA) synthesis and metabolism under normal conditions and in the presence of specific neurotoxins. For details and references, see the main text. Briefly, DA is normally produced from L-DOPA and taken up into synaptic vesicles by the vesicular monoamine transporter 2 (VMAT2). When a neuron is stimulated, vesicular DA is released into the synapse. Released DA is then retrieved into dopaminergic terminals by the plasma membrane DA transporter (DAT) and resequestered into vesicles by VMAT2. One effect of the two neurotoxins 1-methyl-4-phenylpyridinium (MPP+) and amphetamine (AMPH) is to redistribute DA from vesicles to the cytoplasm. Once in the cytoplasm, DA can be oxidized to form DA-quinone, which can inhibit complex I of the mitochondrial respiratory chain, and reactive oxygen species such as hydrogen peroxide (H2O2) and superoxide (O2-), which promote oxidative stress when produced in excess.

 

	MUTATIONS IN THE -SYNUCLEIN GENE ARE LINKED TO FAMILIAL PARKINSON'S DISEASE

TOP ABSTRACT EVIDENCE OF OXIDATIVE STRESS... IS CYTOSOLIC DOPAMINE TOXIC? MUTATIONS IN THE {alpha}... POTENTIAL ROLE OF {alpha}... SYNAPTIC VESICLE RECYCLING: AN... REGULATION OF PLD2 ACTIVITY... FATTY ACID-BINDING PROPERTIES OF... ROLE OF {alpha}-SYNUCLEIN IN... CONCLUDING REMARKS REFERENCES

 
Rare forms of early-onset PD have been linked to mutations in -synuclein and parkin (51). In 1997, Polymeropoulos and colleagues (52) reported a missense mutation in the -synuclein gene, located in chromosome 4q21–23, which led to an alanine-to-threonine conversion at amino acid 53 (A53T) in a large Greek/Italian kindred. One year later, Krüger and colleagues (53) reported a second missense mutation in -synuclein resulting in an alanine-to-proline substitution at residue 30 (A30P) in a family of German origin. These mutations have not been found in other patients with familial PD (54), but single-nucleotide polymorphisms (SNPs) in the promoter region of -synuclein have been associated with an increased risk for the disease (55). Persons carrying -synuclein mutations exhibit autosomal dominant inheritance and develop PD earlier than idiopathic cases (52,56). In addition to the classical neuropathological hallmarks of PD, patients harboring the A53T mutation exhibit neuronal death, gliosis, and extensive Lewy neurites in other parts of the brain including the cortex and hippocampus (57).

-Synuclein is a 140 amino acid protein that is highly conserved among vertebrates and belongs to a family of four closely related members, comprising -, ß- and -synuclein and synoretin (58). The protein can be subdivided into three domains: an amphipathic N-terminal domain (residues 7–87) containing seven imperfect repeats of 11 amino acids each with the core consensus sequence KTKEGV; an internal hydrophobic domain (residues 61–95), also known as the non-amyloid component of Alzheimer's disease plaques (NAC) (59); and an acidic C-terminal domain rich in glutamate and aspartate residues (residues 95–140) (60). Phosphorylation of -synuclein at C-terminal residues, including tyrosine 125 and serine 129, by several kinases appears to regulate different aspects of -synuclein function (61–65).

At low concentrations, -synuclein exists as a ‘random coil’, but adopts an -helical structure upon binding to synthetic phospholipid membranes (66,67). At high concentrations, wild-type and mutant (A53T and A30P) -synuclein can form amyloid fibrils (68,69) as well as non-fibrillar oligomers, also known as protofibrils, which may act as intermediates in the fibrillization process (70,71). Interestingly, -synuclein oligomerization is accelerated by both PD-associated mutations, suggesting that the formation of non-fibrillar oligomers may play an important role in disease pathogenesis (72,73). Even though phosphorylation of -synuclein at serine 129 promotes fibril formation (74), phosphorylation at tyrosine 125 counteracts -synuclein assembly into filaments (62). Lastly, reports that -synuclein is the major component of the insoluble, fibrillar fraction of Lewy bodies suggests that abnormal aggregation of this protein may contribute to neuronal loss in PD (7).

Mutations in the parkin gene have been associated with autosomal recessive, juvenile-onset PD (75). Parkin functions as a ubiquitin (E3) ligase, an enzyme involved in the ubiquitin–proteasome system that is responsible for the degradation of misfolded/damaged proteins (76). Interestingly, parkin has been shown to ubiquinate a higher-molecular-weight form of -synuclein, a function that is abolished by disease-associated mutations in parkin (77). However, a subsequent study reported that parkin actually ubiquinates the -synuclein-interacting protein synphilin 1 and not -synuclein itself (78). Ubiquination of synphilin 1 was also disrupted by familial-linked mutations in parkin. Despite the disparity between these studies, they both suggest that parkin may play a crucial role in -synuclein degradation. Since oxidative damage targets proteins for clearance by the ubiquitin–proteasome system, enhanced OS in PD combined with defects in parkin function could lead to a toxic accumulation of aberrant forms of -synuclein. Indeed, oxidative insults can induce -synuclein aggregation (79,80), suggesting that improper clearance of oxidatively modified -synuclein may play a role in the etiology of PD.

	POTENTIAL ROLE OF -SYNUCLEIN IN SYNAPTIC MAINTENANCE

TOP ABSTRACT EVIDENCE OF OXIDATIVE STRESS... IS CYTOSOLIC DOPAMINE TOXIC? MUTATIONS IN THE {alpha}... POTENTIAL ROLE OF {alpha}... SYNAPTIC VESICLE RECYCLING: AN... REGULATION OF PLD2 ACTIVITY... FATTY ACID-BINDING PROPERTIES OF... ROLE OF {alpha}-SYNUCLEIN IN... CONCLUDING REMARKS REFERENCES

 
-Synuclein is a brain-enriched, neuron-specific protein localized to presynaptic terminals (81–83). It is widely expressed in the neocortex, hippocampus, dentate gyrus, olfactory bulb, striatum, thalamus and cerebellum (81,84). During development, -synuclein is initially expressed in the cell body and gradually redistributes to the neuropil in a fashion similar to other synaptic vesicle proteins (85–88). While targeted deletion of -synuclein in mice does not lead to an overt neuropathological and behavioral phenotype, -synuclein knockout mice do show an enhanced rate of recovery during paired-pulse stimulation, a decrease in the number of synaptic vesicles in the ‘reserve’ pool, impaired neurotransmitter release in response to prolonged, high-frequency stimulation, and an altered response to AMPH (89,90). These results suggest that although not essential for synapse formation or cell survival, -synuclein plays an essential role in synaptic transmission.

Even though studies using transgenic mice overexpressing mutant and wild-type -synuclein have yielded varying results, with only one mouse line exhibiting nigrostriatal pathology to date, transgenic animal models also support the role of -synuclein in synapse preservation. Mice overexpressing wild-type human -synuclein under the control of the human PDGF-ß promoter, which targets expression to the SN, exhibited a >50% loss of dopaminergic terminals in the striatum and a decrease in motor performance (91). In contrast, mice overexpressing A53T mutant human -synuclein under the direction of the mouse Thy-1 promoter, leading to expression of this protein in non-nigral tissues, especially the spinal cord, exhibited striking degeneration of motor axons that was preceded by the denervation of neuromuscular junctions (92). Consequently, these mice showed severe motor deficits. More recently, two independent groups generated mice overexpressing wild-type and mutant forms of -synuclein under the direction of the mouse prion protein (PrP) promoter (93,94), which effectively targeted these proteins to the SN. Despite aberrant accumulation of -synuclein in the midbrain, nigral dopaminergic neurons did not display any neuropathological abnormalities, including loss of striatal dopamine or cell death. Interestingly, mice overexpressing A53T mutant -synuclein, but not those overexpressing the wild-type or A30P mutant protein, exhibited age-dependent motor impairments that were associated with neuropathology in several non-nigral brain regions, including the spinal cord (93,94). Again, motor neurons appeared to undergo extensive axonal degeneration. In conclusion, these rodent models reveal the importance of -synuclein in axonal and synaptic maintenance, despite the disappointing absence of nigral pathology.

In an effort to replicate the regional selectivity observed in PD, several groups have targeted wild-type and mutant forms of -synuclein to catecholaminergic neurons using fragments of the rat tyrosine hydroxylase (TH) promoter. Two lines overexpressing A53T or A30P mutant human -synuclein in the SN did not display Lewy bodies, nigral cell loss, reductions in striatal dopamine or signs of behavioral impairment up to 1 year of age (95,96). In contrast, overexpression of a doubly mutated form of -synuclein containing both the A53T and A30P mutations using a similar promoter resulted in impaired locomotor activity, reductions in striatal dopamine and morphological abnormalities in nigral axons (97). These findings must be interpreted carefully, since only single mutations in the -synuclein gene have been identified in patients with autosomal dominant PD. Nevertheless, transgenic mouse studies suggest that -synuclein is important for axonal and synaptic integrity. Somewhat unexpectedly, they indicate that catecholaminergic neurons are not particularly sensitive to damage induced by mutant -synuclein, which could be due to an overall resistance of murine cells to altered forms of this protein.

	SYNAPTIC VESICLE RECYCLING: AN IMPORTANT FUNCTION FOR -SYNUCLEIN?

TOP ABSTRACT EVIDENCE OF OXIDATIVE STRESS... IS CYTOSOLIC DOPAMINE TOXIC? MUTATIONS IN THE {alpha}... POTENTIAL ROLE OF {alpha}... SYNAPTIC VESICLE RECYCLING: AN... REGULATION OF PLD2 ACTIVITY... FATTY ACID-BINDING PROPERTIES OF... ROLE OF {alpha}-SYNUCLEIN IN... CONCLUDING REMARKS REFERENCES

 
Even though the miniaturization of central nervous system (CNS) synapses has enabled the mammalian brain to increase its computational capacity, it has placed a mechanistic constraint on neurotransmission. New synthesis of synaptic vesicle proteins followed by anterograde transport from the cell body to the terminal would be too slow to sustain neurotransmission during periods of high-frequency stimulation. Thus, synaptic vesicles must form locally at the presynaptic terminal. As opposed to being generated de novo, vesicles are thought to be ‘recycled’ from exocytic vesicles that have fused partially or fully with the plasma membrane (98,99). Two major pathways of vesicle recycling have been described, which operate on different time scales but seem to coexist in individual synapses (98). The classical pathway of vesicle recycling is based on the premise that full fusion is required for the release of neurotransmitter during exocytosis. Following fusion, the recruitment of adaptor molecules to the plasma membrane promotes clathrin coat assembly, which in turn triggers membrane invagination. New vesicles are then liberated from the membrane by the GTPase dynamin (100). This form of recycling, known as clathrin-mediated endocytosis, was first proposed by Heuser and Reese in 1973 (101). Following detachment, newly retrieved vesicles either shed their clathrin coat and are refilled with neurotransmitter (102) or fuse with early endosomes prior to being recycled (103). Alternatively, vesicles can bud directly from plasma membrane invaginations or endosome-like vacuoles by a clathrin- and dynamin-dependent mechanism and immediately re-enter the exocytic cycle following clathrin disassembly (104).

An additional mode of vesicle recycling, proposed in 1973 by Cecarelli and colleagues (105), bypasses the need for clathrin altogether and has been termed ‘kiss-and-run’. In ‘kiss-and-run’ vesicles form a transient pore with the presynaptic membrane that allows the diffusion of neurotransmitter to the extracellular space (106). Vesicles are then detached from the membrane by dynamin and are immediately refilled with neurotransmitter. Thus, synaptic vesicle exocytosis–endocytosis via ‘kiss-and-run’ does not require sorting of membrane components and enables vesicles to undergo fast and efficient recycling. Synapses wherein clathrin-dependent endocytosis has been completely blocked via deletion of endophilin 1 can still sustain release of neurotransmitter at 15–25% of the normal rate during periods of high-frequency stimulation, suggesting that ‘kiss-and-run’ plays an important auxiliary role in vesicle recycling (107).

Like synapsin 1, a synaptic vesicle-associated phosphoprotein that has been implicated in synaptic vesicle recycling (108), -synuclein might also be an important presynaptic regulator of the vesicle cycle. Originally isolated from cholinergic vesicle preparations taken from the electric organ of the ray Torpedo californica (83), -synuclein seems to be equally distributed between cytosolic and intracellular membrane fractions (84,109–112). Morphological studies demonstrate its close proximity to synaptic vesicles, but subcellular fractionation studies suggest that -synuclein is only loosely associated with synaptic vesicles (81,113,114). For example, although present in crude synaptosomal fractions, -synuclein is absent from highly purified synaptic vesicle preparations rich in synaptophysin, a membrane-spanning vesicle protein (84,88,110,115,116). In contrast, in vitro studies using both brain-derived and synthetic phospholipid vesicles show that -synuclein can bind these structures via its N-terminal repeat region, leading to a dramatic change in its secondary structure (66,109,117). Vesicle binding is greatly enhanced by acidic phospholipids such as phosphatidic acid (PA), but not by neutral phospholipids such as phosphatidylcholine (PC) (66). Interestingly, at least 30% acidic phospholipid content is required for maximal binding, but the total content of acidic phospholipids in synaptic vesicles in the brain is <18% (118). This could explain why a great proportion of -synuclein is cytosolic and not vesicle-bound. In addition, phosphorylation of -synuclein by G-protein-coupled receptor kinases can reduce its phospholipid-binding properties (65), suggesting that dynamic changes in its phosphorylation state might tightly regulate the interaction of -synuclein with synaptic vesicle membranes. Alternatively, -synuclein may transiently associate, depending on its phosphorylation state, with early endosomes or plasma membrane invaginations during periods of high-frequency stimulation. Such an interaction would support its role in synaptic vesicle recycling (Fig. 2A).

View larger version (27K): [in this window] [in a new window]   Figure 2. Model whereby -synuclein could regulate vesicle recycling at the synapse. (A) Phospholipase D2 (PLD2) is thought to play a role in vesicle formation at the plasma membrane via the production of phosphatidic acid (PA). This phospholipid has been shown to promote recruitment of adaptor complexes (pink triangles) to donor compartments, a process necessary for the assembly of clathrin molecules (yellow rectangles) and vesicle budding. Translocation of PLD2 to sites of vesicle formation during periods of high-frequency stimulation could be an important step in vesicle recycling. Two mutations in -synuclein (A53T and A30P) have been linked to autosomal dominant Parkinson's disease. These mutations are located in the N-terminal region of -synuclein, which is thought to mediate binding to phospholipid membranes. Thus, mutations in -synuclein could alter its association with, and modulation of, PLD2 and affect vesicle recycling indirectly. (B) Most dopamine molecules are normally sequestered in monoaminergic vesicles at the terminal where they are protected from degradative attack (see Fig. 1). (C) Impaired binding to membrane sites of vesicle recycling arising from mutations in -synuclein could disrupt the ability of this protein to modulate PLD2 activity and, consequently, lead to incomplete vesicle recycling. This may, in turn, result in a shortage of synaptic vesicles available for neurotransmitter storage. In the case of dopaminergic neurons, the outcome would be an accumulation of cytoplasmic dopamine (blue dots), the breakdown of which promotes OS and mitochondrial impairment (Fig. 1).

 
The N-terminal amphipathic region of -synuclein harbors the two mutations (A53T and A30P) linked to autosomal dominant forms of PD (Fig. 2A). Thus, disease pathogenesis could be related to impairment in the ability of -synuclein to bind to phospholipid membranes. The A30P mutation was shown to reduce binding to small phospholipid vesicles, suggesting that substitution of a helix-breaking proline may impair association of -synuclein with phospholipids (109,119). Indeed, the A30P mutation significantly alters the three-dimensional conformation of -synuclein, bringing the two termini closer together (120). Even though the A53T mutation does not seem to disrupt the ability of -synuclein to bind to rat brain or synthetic phospholipid vesicles (109,119,121), it does decrease the efficiency with which it binds to planar lipid bilayers (122). These data bring forth the possibility that while the A30P mutation may affect a specialized function of -synuclein that is contingent on vesicle binding, the A53T mutation could alter a distinct role of -synuclein that depends on its association with different membrane structures such as early endosomes.

Interestingly, protofibrillar -synuclein seems to bind more tightly to phospholipid vesicles than do its monomeric or fibrillar forms (121–123). Unlike the monomeric protein, which adopts an -helical conformation upon vesicle binding, protofibrillar -synuclein adopts a ß-sheet structure when exposed to phospholipids. Addition of protofibrillar, but not fibrillar or monomeric, -synuclein to acidic phospholipid vesicles leads to vesicle permeabilization. Furthermore, incubation with these -synuclein oligomers leads to the selective leakage of small molecules, including dopamine (124). Subsequent studies have shown that A53T and A30P mutations increase the permeabilizing activity of -synuclein, providing an additional pathway whereby mutant -synuclein could promote the accumulation of dopamine in the cytoplasm (124).

	REGULATION OF PLD2 ACTIVITY BY - AND ß-SYNUCLEIN

TOP ABSTRACT EVIDENCE OF OXIDATIVE STRESS... IS CYTOSOLIC DOPAMINE TOXIC? MUTATIONS IN THE {alpha}... POTENTIAL ROLE OF {alpha}... SYNAPTIC VESICLE RECYCLING: AN... REGULATION OF PLD2 ACTIVITY... FATTY ACID-BINDING PROPERTIES OF... ROLE OF {alpha}-SYNUCLEIN IN... CONCLUDING REMARKS REFERENCES

 
In 1998, Jenco and colleagues demonstrated that - and ß-synuclein can selectively inhibit phospholipase D2 (PLD2) and, to a lesser extent, PLD1 (125,126). The PLDs are membrane-bound enzymes that hydrolyze phospholipids such as PC into PA. Their activity is stimulated by exogenous signals, including hormones, neurotransmitters, growth factors, cytokines and other agonists activating cell surface receptors (127,128). While PLD1 is localized to the trans Golgi network, endoplasmic reticulum, endosomes, and secretory vesicles (129,130), PLD2 is primarily localized to the plasma membrane (131,132) (Table 1; Fig. 2A). Both isoforms require phosphatidylinositol 4,5-bisphosphate (PIP₂) as a cofactor (127). PLD1 is activated by several effectors, including protein kinase C (PKC), ADP-ribosylating factor (ARF) and Rho kinases (127). Incidentally, the C-termini of Rho proteins bear some homology to the six-residue core repeat (KTKEGV) of -synuclein (83) (Table 1). In contrast to PLD1, PLD2 cannot be further activated by PKC or Rho family members and is only modestly activated by ARF (132,133) (Table 1). PLD1 can be inhibited by clathrin assembly protein 3 (AP3), which promotes budding of synaptic-like vesicles from endosomes by recruiting clathrin to this compartment (134–136), by fodrin, a member of the spectrin family that mediates plasma membrane reorganization via interactions with the actin cytoskeleton (137), by synaptojanin, an enzyme that hydrolyzes PIP₂ and participates in clathrin coat recruitment and endocytosis at the plasma membrane (138–140), and by amphiphysins 1 and 2, which are synaptic vesicle proteins that bind clathrin, AP2 and dynamin and are essential for clathrin-mediated endocytosis (141). Even though PLD2 exhibits a greater basal activity than PLD1, in vivo PLD2 activity seems to be masked by negative regulators, including - and ß-synuclein (125,126,132,133,141) and amphiphysins 1 and 2 (141). In conclusion, the selective regulation of PLD1 and PLD2 by proteins involved in clathrin-mediated endocytosis supports a role for these two enzymes in synaptic vesicle recycling.

View this table: [in this window] [in a new window]   Table 1. Comparison between phospholipase D1 and phospholipase D2

 
Even though most studies aimed at understanding the function of PLD1 and 2 have been conducted in non-neuronal cells types, these findings could shed important light on the role of these enzymes in neurons. Following activation by exogenous stimuli, PLDs appear to stimulate secretion in non-neuronal cells by regulating membrane vesicle trafficking (142). In neurons, they also appear to control neurotransmitter release (143). The product of PLD activity is the membrane phospholipid PA, which, in addition to functioning as an intracellular messenger, can promote the recruitment of cytosolic adaptor complexes to donor membranes, for example AP1 to the trans Golgi network, AP2 to the plasma membrane and AP3 to endosomes (142,144,145). This, in turn, facilitates the recruitment of coatomer or clathrin coat proteins and triggers budding of vesicles from these compartments (146). Consistent with its localization to perinuclear regions, PLD1 appears to stimulate vesicle biogenesis in the early secretory pathway (128). For instance, addition of human PLD1 to permeabilized cells stimulates budding of nascent secretory vesicles from the trans Golgi network (147). Similarly, production of PA by PLD2 may regulate vesicle formation at or near the plasma membrane. For example, serum-stimulated fibroblasts exhibit a redistribution of PLD2 from the plasma membrane to submembraneous vesicles resembling early endosomes (132). In addition to promoting the recruitment of adaptor complexes to membrane sites of vesicle formation, PA may also promote vesicle endocytosis at the plasma membrane by altering membrane curvature. For instance, endophilin 1, a cytosolic enzyme that converts lysophosphatidic acid, an inverted-cone-shaped fatty acid, to PA, a cone-shaped phospholipid, promotes positive bilayer curvature and vesicle fusion (148). Interestingly, removal of endophilin 1 in Drosophila melanogaster results in a blockade of clathrin-mediated endocytosis and depletion of synaptic vesicles (107).

What is the likelihood that -synuclein could regulate synaptic vesicle recycling at the presynaptic terminal via interactions with PLD2? Recently, -synuclein was shown to physically interact with and inhibit both PLD1 and PLD2 through its N-terminal repeat region (125). Given its high affinity for acidic phospholipids such as PA, -synuclein may act as a feedback regulator of PA synthesis by inhibiting PLD2 (66) (Fig. 2). This function of -synuclein may be tightly regulated by intracellular kinases, which can phosphorylate the protein at different sites. Interestingly, phosphorylation of -synuclein by G-protein-coupled receptor kinases not only reduces phospholipid binding but also lowers the ability of -synuclein to inhibit PLD2 (65). Since the activity of G-protein receptor kinases is tightly regulated by calcium-sensor proteins (149,150), elevations in intracellular calcium following periods of high-frequency stimulation may lead to activity-dependent phosphorylation of -synuclein. This would, in turn, weaken the interaction of -synuclein with endosomal membranes and reduce its tonic inhibition of PLD2. Since the demand for synaptic vesicles would be expected to increase during periods of ongoing neuronal activity, kinase-mediated phosphorylation of -synuclein may promote vesicle recycling via disinhibition of PLD2. Indeed, many proteins involved in synaptic vesicle recycling, including synapsin 1, are also regulated by phosphorylation (151). Perhaps mutations in -synuclein alter the phosphorylation state of this protein and impair its ability to modulate PLD2. This would invariably lead to changes in vesicle recycling that could culminate in a shortage of synaptic vesicles available for neurotransmitter storage and release.

When subjected to a pair of consecutive stimuli, a neuron's response to the second stimulus tends to be significantly smaller. This ‘paired-pulse depression’ (PPD) may result from activity-dependent inactivation of the exocytotic machinery, which could, in turn, be mediated by a depletion of presynaptic vesicles available for release, activation of presynaptic autoreceptors, or postsynaptic receptor desensitization. Striatal terminals from -synuclein knockout mice exhibit a decrease in PPD, raising the possibility that -synuclein acts as a negative regulator of transmitter release (89). Via its inhibition of PLD2, non-phosphorylated -synuclein may suppress vesicle formation during periods of low neuronal activity. It is feasible that -synuclein mutations could alter the conformational state of the protein such that it can no longer be properly phosphorylated in response to nerve stimulation. This would, in turn, lead to tonic inhibition of PLD2 by -synuclein, resulting in impaired vesicle recycling. Interestingly, suppression of -synuclein in cultured hippocampal neurons by antisense oligonucleotide technology to a reduction in the number of vesicles in the ‘reserve pool’ (152), a larger population of inactive vesicles that is recruited during periods of high frequency stimulation and is distinct from the ‘readily releasable’ pool located at the active zone. Vesicles in the ‘reserve’ pool may originate from an early endosomal compartment, thus a depletion in this pool could signify a defect in endosomal recycling. Interestingly, -synuclein-depleted cells also exhibit a decrease in the expression of synapsin, a protein essential for synaptic vesicle recycling (108,153). Lastly, recent studies using a new line of -synuclein knockout mice further support the role of -synuclein in vesicle recycling. Hippocampal neurons from -synuclein-null animals displayed a decrease in the number of vesicles in the ‘reserve’ pool and exhibited a reduced synaptic response following prolonged high-frequency stimulation (90). In this paradigm, the pool of vesicles in the active zone would be depleted, thus increasing the demand for vesicle recycling.

	FATTY ACID-BINDING PROPERTIES OF -SYNUCLEIN

TOP ABSTRACT EVIDENCE OF OXIDATIVE STRESS... IS CYTOSOLIC DOPAMINE TOXIC? MUTATIONS IN THE {alpha}... POTENTIAL ROLE OF {alpha}... SYNAPTIC VESICLE RECYCLING: AN... REGULATION OF PLD2 ACTIVITY... FATTY ACID-BINDING PROPERTIES OF... ROLE OF {alpha}-SYNUCLEIN IN... CONCLUDING REMARKS REFERENCES

 
The vesicle-binding, amphipathic N-terminal region of -synuclein bears significant homology to the lipid-binding class A apolipoproteins A2 and C1–3, which are proteins involved in lipid transport (154). These lipid-binding proteins also constitute the major component of high-density lipoproteins (HDL) (155). Like -synuclein, apolipoproteins have a highly unordered structure in the absence of lipids and adopt an -helical structure upon lipid binding (156). Incidentally, this conformational instability increases their propensity to form amyloid (157). Various apolipoproteins co-localize with amyloid and, like -synuclein, are the major components of Alzheimer's disease plaques and Lewy bodies (7,59,158).

Recent evidence suggests that -synuclein might have fatty acid-binding protein (FBAP) properties. Intracellular FABPs bind long-chain fatty acids and participate in fatty acid metabolism and transport, shuttling fatty acids from the aqueous environment to different intracellular destinations (159). In addition to gangliosides and cholesterol, fatty acids are highly enriched in synaptic vesicles (160,161). Not only does -synuclein resemble FABPs in size, but short amino acid stretches in its N and C termini share 55% and 67% homology, respectively, with a cytosolic fatty acid-binding motif found in FABPs (112). -Synuclein has been shown to bind the fatty acid oleic acid (chosen as an ‘assay’ of FABP function) in a dose-dependent and competitive fashion (112). Given its lipid-binding properties and transient association with vesicular membranes, -synuclein could transfer fatty acids to sites of synaptic vesicle formation (e.g. early endosomes). Alternatively, as a lipid chaperone, it could regulate the turnover or local organization of polyunsaturated fatty acid acyl groups, which have been implicated in clathrin-mediated endocytosis (107,162). Unlike native, monomeric -synuclein, which exists as a random coil in solution or an helix when bound to acidic phospholipid vesicles, FABPs are flattened, 10-stranded ß barrels that harbor an internal, water-filled cavity necessary for fatty acid transport (163). When bound to synthetic vesicles containing certain polyunsaturated fatty acid acyl groups, -synuclein multimerizes and adopts a ß-rich structure (164–167). Thus, -synuclein oligomers may adopt a similar structure to FABPs when inserted into membranes and bind fatty acids like oleic acid via the formation of a water-filled pocket. In conclusion, -synuclein may regulate synaptic vesicle recycling by acting as a presynaptic FABP or fatty acid modulator, transferring fatty acids to membrane compartments where vesicles are formed.

	ROLE OF -SYNUCLEIN IN DOPAMINE HOMEOSTASIS

TOP ABSTRACT EVIDENCE OF OXIDATIVE STRESS... IS CYTOSOLIC DOPAMINE TOXIC? MUTATIONS IN THE {alpha}... POTENTIAL ROLE OF {alpha}... SYNAPTIC VESICLE RECYCLING: AN... REGULATION OF PLD2 ACTIVITY... FATTY ACID-BINDING PROPERTIES OF... ROLE OF {alpha}-SYNUCLEIN IN... CONCLUDING REMARKS REFERENCES

 
As a PLD2 modulator and/or FABP, -synuclein may regulate vesicle recycling at the nerve terminal. Altered function of -synuclein brought about by genetic mutations could result in a shortage of monoaminergic vesicles, which would, in turn, lead to a gradual accumulation of dopamine in the cytoplasm. Given the propensity of the catecholamines to oxidize, a build-up of toxic dopamine metabolites in the cytoplasm could trigger dopaminergic cell death by a number of mechanisms, including oxidative stress and inhibition of mitochondrial complex I (see above). Indeed, recent data suggest that, similarly to AMPH and MPP⁺, mutant -synuclein may increase levels of cytoplasmic dopamine. Studies in our laboratory using a newly characterized human mesencephalic cell line that can be terminally differentiated to yield a high proportion of mature dopamine neurons expressing high levels of wild-type -synuclein indicate that -synuclein may be important for dopamine storage. In this system, lentivirus-mediated overexpression of A53T mutant human -synuclein led to a decrease in the levels of VMAT2, reduced dopamine release in response to high potassium stimulation and enhanced release in response to AMPH (Fig. 3) (168). Mutant cells also exhibited higher levels of cytoplasmic dopamine immunofluorescence and increased production of superoxide radicals (Fig. 3). These data suggest that A53T mutant -synuclein leads to impaired vesicular dopamine storage, culminating in cytosolic dopamine accumulation and OS. In a parallel study, apoptosis induced by overexpression of A53T mutant -synuclein in primary human mesencephalic neurons could be blocked by depleting cells of intracellular dopamine, supporting the notion that the pathogenicity of mutant -synuclein is indeed dopamine-dependent (169).

View larger version (29K): [in this window] [in a new window]   Figure 3. Human dopaminergic (MESC2.10) neurons expressing A53T mutant -synuclein exhibit altered intracellular dopamine homeostasis. (A) MESC2.10 cells are immortalized human embryonic mesencephalic neurons that can be terminally differentiated by turning off the tetracycline-regulated expression of v-myc. Exposure to tetracycline, dibutyryl cAMP and glial-derived neurotrophic factor for 6 days induces a dopaminergic phenotype, with >80% of cells expressing tyrosine hydroxylase, DAT and ß-tubulin. In these experiments, A53T mutant human -synuclein was introduced into differentiated MESC2.10 cells by lentiviral (LV) transfer. Cells expressing the mutant protein showed a decrease in 3H-dopamine (3H-DA) release in response to 60 mM KCl but enhanced release in response to 50 µM AMPH after 20 min of drug exposure. Values are expressed as % of LV-GFP control cells, which express high levels of wild-type human -synuclein. (B) MESC2.10 cells also exhibited increased cytoplasmic dopamine immunofluorescence and higher levels of superoxide radicals as detected by the redox-sensitive dye dihydroethidium. Cells expressing the mutant protein were fixed and processed with an antibody against dopamine (coupled to a fluorescent secondary conjugate). The basal cytoplasmic dopamine immunofluorescence from >50 cells per experiment was measured by confocal microscopy and averaged. Values are expressed as % of LV-GFP transduced cells. For superoxide detection, cells were incubated with 3 µM dihydroethidium for 20 min at 37°C and fixed with 4% paraformaldehyde. Cytoplasmic dihydroethidium fluorescence was measured as stated above. All graphs denote the mean±SEM. *P<0.01 compared with untreated cells; # P<0.01 compared with LV-GFP cells (two-way ANOVA with post hoc Student's t-test).

 
In addition to regulating dopamine storage, -synuclein could modulate intracellular dopamine handling through interactions with proteins that regulate dopamine synthesis and uptake. For instance, direct binding of -synuclein to the DAT via its C-terminal domain seems to enhance extracellular dopamine uptake by increasing the number of functional transporters at the cell surface (170). Furthermore, in vitro studies suggest that -synuclein can directly bind to and inhibit tyrosine hydroxylase (TH) (171). Overexpression of -synuclein in a mouse mesencephalic cell line revealed a physical interaction between -synuclein and TH that was coupled to a reduction in TH activity and dopamine synthesis. Altered regulation of TH by -synuclein, however, may not play a role in the pathogenesis of PD, since this inhibitory effect of -synuclein on dopamine biosynthesis was unaltered by overexpression of the A53T mutant protein. Interestingly, -synuclein bears some homology with 14-3-3 proteins (172), a family of brain-enriched molecular chaperones found in presynaptic terminals (173–175). In addition to modulating the activity of cellular enzymes, sequestering proteins and acting as scaffolds bringing protein targets together (176), 14-3-3 proteins appear to control vesicle transport and exocytosis at the presynaptic terminal via interactions with the actin cytoskeleton (173,177,178). Incidentally, 14-3-3 proteins can also bind tyrosine hydroxylase (179), but, unlike -synuclein, they activate the enzyme not inhibit it. Interestingly, high-molecular-weight complexes immunoreactive for both -synuclein and 14-3-3 have been detected in the SN of PD patients (169). This, together with the presence of 14-3-3 proteins in Lewy bodies, may suggest an attempt of these molecular chaperones to sequester aberrant forms of -synuclein in diseased nigral neurons.

	CONCLUDING REMARKS

TOP ABSTRACT EVIDENCE OF OXIDATIVE STRESS... IS CYTOSOLIC DOPAMINE TOXIC? MUTATIONS IN THE {alpha}... POTENTIAL ROLE OF {alpha}... SYNAPTIC VESICLE RECYCLING: AN... REGULATION OF PLD2 ACTIVITY... FATTY ACID-BINDING PROPERTIES OF... ROLE OF {alpha}-SYNUCLEIN IN... CONCLUDING REMARKS REFERENCES

 
What is the likelihood that altered synaptic vesicle recycling could play a pathogenic role in the development of PD? In this review, we have presented accumulating evidence that -synuclein could regulate vesicle recycling via its inhibition of PLD2 and/or its ability to bind fatty acids. Since dopamine is a highly cytotoxic neurotransmitter, its improper sequestration could potentially lead to dopamine-dependent OS and cell death. Even though mutations in -synuclein are a rare cause of PD, the intriguing possibility that this protein could be involved in synaptic vesicle recycling suggests that improper sequestration of dopamine could be an important mechanism leading to dopaminergic cell loss in sporadic, as well as genetic, forms of the disease. Mutations in any number of genes that encode proteins involved in vesicle recycling could result in small, seemingly unnoticeable changes in the ability of neurons to properly store different neurotransmitters, not just dopamine, into synaptic vesicles. Such changes may only become apparent during periods of ongoing neuronal activity, when large amounts of neurotransmitter must be synthesized, stored and released. Cytoplasmic degradation of unstored catecholamines, in particular dopamine, may lead to protracted accumulation of toxic metabolites that would, in turn, trigger neuronal dysfunction and eventually cell death.

	ACKNOWLEDGEMENTS

 
The authors are grateful to Drs David Sulzer and Richard Palmiter for critical reading of the manuscript. We acknowledge Bengt Mattson for help with the illustrations. The work mentioned in this review was supported by grants from the Swedish Research Council (to P.B.), the Swedish Society for Medical Research (J.L.), Parkinsonsförbundets Forskningsfond (J.L.) and a fellowship from The Parkinson's Disease Foundation (J.L.).

	FOOTNOTES

 
^* To whom correspondence should be addressed at: Section for Neuronal Survival, Wallenberg Neuroscience Center, Lund University, BMC A10, 221 84 Lund, Sweden. Tel: +46 462220529; Fax: +46 462220531; Email: julie.lotharius{at}mphy.lu.se

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TOP ABSTRACT EVIDENCE OF OXIDATIVE STRESS... IS CYTOSOLIC DOPAMINE TOXIC? MUTATIONS IN THE {alpha}... POTENTIAL ROLE OF {alpha}... SYNAPTIC VESICLE RECYCLING: AN... REGULATION OF PLD2 ACTIVITY... FATTY ACID-BINDING PROPERTIES OF... ROLE OF {alpha}-SYNUCLEIN IN... CONCLUDING REMARKS REFERENCES

 
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