Human Molecular Genetics, 2001, Vol. 10, No. 9 919-926
© 2001 Oxford University Press
Inducible expression of mutant 
-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis
1Department of Psychiatry, 2Department of Neuroscience, 3Department of Neurology, 4Department of Physiology and 5Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA, 6Departamento de Anatomia, Universidade Federal do Rio de Janeiro, Ilha do Fundao, Brazil and 7Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Received 18 December 2000; Revised and Accepted 26 February 2001.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Parkinson’s disease (PD) is a common progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra. Although mutations in
-synuclein have been identified in autosomal dominant PD, the mechanism by which dopaminergic neural cell death occurs remains unknown. Proteins encoded by two other genes in which mutations cause familial PD, parkin and UCH-L1, are involved in regulation of the ubiquitin-proteasome pathway, suggesting that dysregulation of the ubiquitin-proteasome pathway is involved in the mechanism by which these mutations cause PD. We established inducible PC12 cell lines in which wild-type or mutant -synuclein can be de-repressed by removing doxycycline. Differentiated PC12 cell lines expressing mutant -synuclein showed decreased activity of proteasomes without direct toxicity. Cells expressing mutant -synuclein showed increased sensitivity to apoptotic cell death when treated with sub-toxic concentrations of an exogenous proteasome inhibitor. Apoptosis was accompanied by mitochondrial depolarization and elevation of caspase-3 and -9, and was blocked by cyclosporin A. These data suggest that expression of mutant -synuclein results in sensitivity to impairment of proteasome activity, leading to mitochondrial abnormalities and neuronal cell death. |
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Parkinson’s disease (PD) is a common progressive neurodegenerative disorder, characterized by tremor, muscle rigidity and bradykinesia. Post-mortem examination shows loss of dopaminergic neurons in the substantia nigra and the presence of inclusions termed Lewy bodies (1–5). Mutations in
-synuclein (A30P and A53T) cause autosomal dominant PD (6,7), which shares many of the phenotypic findings seen in sporadic PD. In both autosomal dominant and sporadic PD, there is deposition of -synuclein in Lewy bodies (8–10). In addition, it has been recently reported that transgenic mice and flies expressing human wild-type or mutant -synuclein show neuronal dysfunction, degeneration and abnormal cellular accumulation of -synuclein (11–14), indicating that -synuclein may have a role in the pathogenesis of both familial and sporadic PD. Several lines of evidence suggest a role for the ubiquitin-proteasome pathway in the pathogenesis of PD. Proteasome subunits colocalize in Lewy bodies (15). The causal gene product for autosomal recessive juvenile parkinsonism (AR-JP), parkin, acts as an E3 ubiquitin-protein ligase (16–18). Due to disruption of parkin’s ubiquitination function, accumulation of target proteins normally degraded by the ubiquitin-proteasome pathway may contribute to the development of AR-JP. In addition, a missense mutation in the ubiquitin C-terminal hydrolase L1 (UCH-L1) has been identified in another family with PD (19). UCH-L1 is thought to produce ubiquitin by cleaving polymeric ubiquitin or releasing ubiquitin from small adducts such as glutathione and cellular amines (20). These findings suggest that dysregulation of the ubiquitin-proteasome pathway is involved in the pathogenesis of PD.
It has been postulated that mitochondrial dysfunction may also have a role in the pathogenesis of PD (21–25). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been reported to cause acute and irreversible parkinsonism in humans, and 1-methyl-4-phenylpyridinium (MPP+), a metabolite of MPTP, inhibits mitochondrial complex I, one of the enzymes involved in oxidative phosphorylation (26–28). In addition, cells overexpressing wild-type -synuclein show mitochondrial dysfunction (29). However, it is not clear if there is a relation between PD-associated mutations of -synuclein, cellular abnormalities involving proteasome dysfunction, mitochondrial changes and neuronal degeneration. To study how mutant -synuclein is involved in the pathogenesis of PD, we have created inducible PC12 cell models in which expression of either wild-type or A30P mutant -synuclein can be induced. We used PC12 cells for creating the cell models, because PC12 cells are known to synthesize and secrete dopamine, and can be differentiated into a neuron-like phenotype by nerve growth factor (30). We now report that expression of mutant -synuclein decreases proteasome activity and renders cells vulnerable to mitochondria-dependent apoptosis.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Establishment of
-synuclein inducible cell linesTo study how
-synuclein is involved in the pathogenesis of PD, we have established inducible -synuclein PC12 cell lines using the Tet-Off gene expression system. Regulation of the system is achieved through the tetracycline-controlled transactivator (tTA). The cells showed expression of the transgene in the absence of doxycycline (Dox) (induced condition), and no expression in the presence of Dox (uninduced condition) (Fig. 1A and B). We confirmed that there was no significant difference in the expression level of -synuclein in each cell line using duplicate samples of cell cultures as measured by densitometer (data not shown). Two mutations (A30P and A53T) of -synuclein cause autosomal dominant PD (6,7). PC12 cells are derived from rat pheochromocytoma, and the rat carries the T53 allele as its normal sequence. Because human A53T mutant -synuclein may be better tolerated in rat cells, we chose to establish A30P mutant -synuclein inducible cell lines. In addition, data from -synuclein transgenic flies indicate that flies expressing A30P mutant -synuclein show a significantly greater phenotype than those expressing A53T mutant -synuclein (12).
|
Expression of mutant
-synuclein decreases proteasome activity and increases sensitivity to cell death by proteasome inhibitionWe measured proteasome activities in wild-type and mutant
-synuclein inducible cell lines in both induced and uninduced conditions. We also used Tet-Off PC12 cells containing only pTet-Off plasmid, and a Tet-Off inducible cell line expressing full length huntingtin with a normal length polyglutamine tract (FL-23Q) as controls. In cells expressing mutant -synuclein, chymotryptic-like, tryptic-like and postacidic activities of proteasome were significantly decreased by 22.1, 17.7 and 24.6%, respectively (Fig. 2). Although wild-type cell lines also showed decreased proteasome activities to some extent, there was no significant difference compared with control cell lines.
|
To test the toxicity of mutant
-synuclein, we used lactacystin, a proteasome inhibitor, since cells expressing mutant -synuclein show proteasomal hypoactivity. Lactacystin is the most selective proteasome inhibitor and even at high concentrations and long incubation times, it does not strongly inhibit other proteases (31). In the absence of lactacystin, cell lines did not show significant differences in cell death in either induced or uninduced conditions. In contrast, in the presence of lactacystin, mutant cell lines show significantly more cell death (1.4- and 2.4-fold increases in the presence of 5 and 10 µM lactacystin, respectively) than wild-type cell lines in induced conditions as measured by the trypan blue assay (Fig. 3). Although wild-type cell lines showed increased toxicity in the presence of lactacystin, the amount of cell death was significantly less than in mutant cell lines. We also used Tet-Off inducible cells expressing truncated huntingtin with an expanded polyglutamine tract (N63-148Q) as an additional control expressing a toxic protein. N63-148Q alone caused increased cell toxicity in induced conditions compared with uninduced conditions. However, the cells expressing mutant huntingtin did not show increased toxicity in the presence of lactacystin (Fig. 3).
|
Proteasome inhibition induces apoptotic cell death in cells expressing mutant
-synucleinThe manner in which cell death occurred was examined by nuclear morphology using 4'-6-diamidinophenylidole (DAPI) nuclear staining. We found that cell death was primarily apoptotic (Fig. 4A). Apoptotic cell death was substantially increased in induced mutant cell lines in a lactacystin concentration dependent manner (3.7- and 7.9-fold increases in the presence of 5 and 10 µM lactacystin, respectively) when compared with wild-type cell lines (Fig. 4B). Wild-type cell lines also showed an increase in the number of apoptotic cells in the presence of lactacystin, though the amount of apoptotic cells was significantly smaller than in mutant cell lines. As a further control for the effect of expression of a non-toxic protein, we examined a FL-23Q cell line. Toxicity in either induced or uninduced conditions were the same in pTet-Off and FL-23Q cell lines (Fig. 4B).
|
Caspase-3 and -9 are activated in cells expressing mutant
-synuclein in the presence of a protesome inhibitorApoptotic cell death is often associated with caspase-3 activation (32,33). After treatment with lactacystin, caspase-3 activity was much greater in induced mutant cell lines (2- and 2.4-fold increases in the presence of 5 and 10 µM lactacystin, respectively) compared with untreated cells (Fig. 5A). We also monitored caspases that are upstream of caspase-3. There were no significant differences between wild-type and mutant cell lines in caspase-8 activity (Fig. 5B). In contrast, caspase-9 was activated to a greater extent in mutant cell lines (2.6- and 3.2-fold increases in the presence of 5 and 10 µM lactacystin, respectively) compared with untreated cells (Fig. 5C).
|
Expression of mutant
-synuclein induces mitochondrial depolarization in the presence of a proteasome inhibitor and cyclosporin A (CsA) inhibits mitochondrial depolarization and apoptotic cell deathWe studied mitochondrial depolarization using the fluorescent dye 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1). JC-1 produces one of two emissions (red and green), depending on the mitochondrial membrane potential. The red and green signals represent polarized and depolarized mitochondria, respectively. We assessed the effect of lactacystin in pTet-Off, FL-23Q, wild-type and mutant
-synuclein cell lines. In the absence of lactacystin, there were no differences in mitochondrial membrane potentials in all cells examined. In contrast, mutant cell lines showed significant increases in mitochondrial depolarization by 19.9 and 30.5% in the presence of 5 and 10 µM lactacystin, respectively (Fig. 6A and B). Wild-type cell lines showed an increase in mitochondrial depolarization in the presence of lactacystin, but the depolarization was significantly smaller than in mutant cell lines.
|
To assess the possibility of a causal role for mitochondrial dysfunction in cell death induced by mutant
-synuclein, we used CsA. CsA binds to a mitochondrial form of cyclophilin, and inhibits the mitochondrial permeability transition (MPT) (33,34). MPT induces mitochondrial depolarization, and is itself augmented by depolarization. MPT participates in the initiation of apoptosis (24,33,35,36). Treatment with CsA reduced mitochondrial depolarization (25.6 and 15.9% in the presence of 0.5 and 2.0 µM CsA, respectively) and apoptotic cells (9.3 and 6.0% in the presence of 0.5 and 2.0 µM CsA, respectively) in cells expressing mutant -synuclein in the presence of lactacystin (Fig. 6C and D). |
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
This report shows that mutant
-synuclein decreases proteasome activity, leading to increased sensitivity to mitochondria-dependent apoptosis. To study how mutant -synuclein is involved in neuronal degeneration in PD, we have established inducible -synuclein PC12 cell lines. Inducible cell lines are useful for cell toxicity models because expression of the toxic protein can be suppressed during clonal selection. After creating cell lines, expression of the transgene can be induced. Furthermore, cell toxicity in induced conditions can be compared with that in uninduced conditions. Here we compared proteasome activity and cell toxicity in induced conditions with those in uninduced conditions. After 7 days of induction and differentiation in the absence of a proteasome inhibitor, we found decreased proteasome activity in cells expressing mutant -synuclein. Although the mechanism by which mutant -synuclein decreases proteasome activity remains to be identified, it is possible that mutant -synuclein directly affects the proteasome complex because it has been reported recently that -synuclein interacts with a subunit of proteasome regulatory complexes (37).
Proteins encloded by other causal genes of familial PD, parkin and UCH-L1, are a ubiquitin-protein ligase and a deubiquitinating enzyme, respectively (16,19). In addition, proteasome subunits co-localize in Lewy bodies, and gad mice, which have an in-frame deletion of UCH-L1, show altered function of the ubiquitin system and neurodegeneration (15,38). Moreover, it has been reported recently that proteasomal function is impaired in the substantia nigra in sporadic PD, suggesting that dysregulation of the ubiquitin-proteasome pathway contributes to the pathogenesis of not only familial cases but also sporadic cases of PD (39). In the present study, our data suggest small but significant decreased proteasome activity as a result of mutant -synuclein expression. In addition, we detected increased cell death in differentiated PC12 cells expressing mutant -synuclein in the presence of a proteasome inhibitor. These data suggest that aberration in the proteolytic pathway plays a role in the pathogenesis of PD. In the absence of a proteasome inhibitor, we did not detect significantly increased cell death in cells expressing mutant -synuclein. It has been reported that inducible expression of another type of mutant -synuclein (A53T) did not increase cell toxicity unless cells were subjected to exogenous stress (40). To detect cell toxicity induced by mutant -synuclein, it may be necessary to add an additional stress such as oxidative stress, administration of dopamine or proteasome inhibition.
Proteasome inhibition results in accumulation of molecules normally degraded by the ubiquitin-proteasome pathway such as p53, NF
B and Bax (41–43). These molecules appear to participate in apoptotic signaling. In cells expressing mutant -synuclein, these or related molecules might tend to accumulate because of decreased proteasome activity compared with non- mutant cells, causing apoptotic cell death.
It has been reported that caspase-3 is a direct upstream activator of deoxyribonucleases responsible for DNA fragmentation during apoptosis (44,45). Caspase-3 activation is involved in both mitochondria-dependent and Fas-induced apoptosis. Caspase-9 is an upstream activator of caspase-3, and activation of caspase-9 is involved in mitochondrial-dependent apoptosis (46,47). Although caspase-8 is also an upstream activator of caspase-3, caspase-8 is involved in Fas-induced apoptosis (48–50). According to our data, caspase-9 was activated by expression of mutant -synuclein, indicating mitochondria-dependent apoptosis induced by mutant -synuclein.
It has been reported previously that mitochondrial dysfunction may have a role in the pathogenesis of neurodegenerative diseases such as PD (21–25), Alzheimer’s disease (AD) (51–53) and Huntington’s disease (HD) (33,54). Mutations in presenilin-1 increase the vulnerability of neural cells to mitochondrial toxins (52), and lymphoblasts from HD patients are abnormally susceptible to the induction of mitochondrial depolarization and apoptosis induced by apoptogenic stimuli (33). However, a relation between mutations of -synuclein and mitochondrial dysfunction had not been shown. Here we report that cells expressing mutant -synuclein showed a selective increase in mitochondrial depolarization and apoptotic cell death in the presence of a proteasome inhibitor. In addition, mitochondrial depolarization and apoptotic cell death were reduced by CsA, suggesting a causal role for mitochondrial dysfunction in cell death induced by mutant -synuclein. Although treatment with CsA reduced the cell toxicity, the post-treatment values were not reduced to control levels. This finding suggests that other pathways beside CsA-sensitive apoptosis are involved in cell death induced by mutant -synuclein. Wild-type cell lines showed decreased proteasome activity and cell viability, and increased mitochondrial dysfunction, consistent with previously published reports using transgenic mice, flies and stable cell lines (11,12,29). This result may be relevant to PD, since most patients with PD do not have mutations in -synuclein, and have wild-type -synuclein incorporated into Lewy bodies. However, mutant -synuclein was significantly more toxic in our experiments than wild-type.
Several lines of evidence suggest that apoptotic cell death contributes to the pathogenesis of PD (55–61). Expression of -synuclein induces mitochondrial dysfunction (29). In addition, it has been reported that mutant forms of -synuclein increase cell toxicity (62,63). Here we report that the mutant form of -synuclein can decrease proteasome activity, leading to increased sensitivity to mitochondria-dependent apoptosis. These data suggest that dysregulation of the ubiquitin-proteasome pathway may be involved in cell death induced by mutant -synuclein.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Cell culture and inducible cell lines
Cells were grown in DMEM containing 10% FBS and 5% horse serum in a 5% CO2 atmosphere. To create Tet-Off PC12 cell lines inducibly expressing either wild-type or A30P mutant
-synuclein, PC12 Tet-Off cells containing pTet-Off were purchased from Clontech. Tet-responsive -synuclein expression constructs were made by cloning full-length cDNA of wild-type or A30P mutant -synuclein into pTRE (Clontech). These -synuclein constructs were cotransfected into PC12 Tet-Off cells with pTK-Hyg (Clontech) at a 10:1 molar ratio. Single colonies were obtained by limiting dilution with 100 µg/ml G418 and 200 µg/ml hygromycin B (Clontech) in the presence of 200 ng/ml Dox for 2–3 weeks. Clones were analyzed for the expression of -synuclein by western blotting.
Immunocytochemistry and western blot
Tet-Off inducible cell lines were incubated with or without 200 ng/ml Dox for uninduced conditions or induced conditions, respectively. After 7 days of induction and differentiation, cells were fixed with 4% paraformaldehyde for 30 min and permeabilized with 0.2% Triton X-100 for 15 min at room temperature and processed as described (33). Cells were labelled with anti--synuclein antibody (1:100; Transduction Laboratories) and nuclei were stained with DAPI, and analyzed by confocal microscopy (Zeiss, LSM 410). To confirm the expression of -synuclein by western blotting, an anti--synuclein antibody (1:1000; Transduction Laboratories) was used, and the blots were visualized by ECL western blotting detection reagent (Amersham Pharmacia Biotech).
Proteasome activity
Cells were grown in DMEM containing 1.0% FBS, 0.5% horse serum and 50 ng/ml nerve growth factor in a 5% CO2 atmosphere. Proteasome activity was measured 7 days after induction and differentiation. The fluorogenic substrates, Suc-LLVY-AMC, Z-LLE-AMC and Boc-LRR-AMC, were used to measure the chymotryptic-like, tryptic-like and postacidic activities, respectively. The proteasome activities were monitored by the fluorescence activity (
ex: 380 nm; em: 460 nm) (64).
Cell viability analysis
To assess cell viability, we used the trypan blue exclusion assay and DAPI nuclear staining. All cells with the exception of N63-148Q were incubated with or without 5 or 10 µM lactacystin for 15 h after 7 days of induction and differentiation. Because N63-148Q shows cell toxicity starting from 3 days after induction and differentiation, lactacystin was added to the cell line at 3 days post-induction/differentiation. We counted the percentage of blue-stained cells among total cells (2400–3600 cells in total) in the trypan blue exclusion assay. In addition, apoptotic nuclei were analyzed morphologically after staining with DAPI, and percentages of apoptotic cells were obtained among total cells (1200–1800 cells in total).
Caspase activity
Cells were incubated with or without 5 or 10 µM lactacystin for 15 h after 7 days of induction and differentiation. Caspase-3 activity was measured by a colorimetric kit (Clontech). The peptide substrate conjugated with p-nitroanilide was used. The extent of cleavage was monitored by the change in absorbance at 405 nm and normalized to total protein. Activities of caspase-8 and -9 were measured by similar methods using a colorimetric kit (Biovision).
Mitochondrial membrane potential
Cells were incubated with or without 5 or 10 µM lactacystin for 15 h after 7 days of induction and differentiation. In living cells, JC-1 (Molecular Probes) was used to monitor mitochondrial membrane potentials. Cells were incubated with JC-1 (10 µg/ml) for 10 min at 37°C according to the manufacturer’s instructions. JC-1 exhibits membrane-potential-dependent accumulation in mitochondria and is indicated by a fluorescent emission shift from green to red. Mitochondrial depolarization is indicated by an increase in the green:red fluorescence intensity ratio. We monitored the green:red ratio using confocal micro-scopy and analyzed as described (33,65).
Statistics
Data were presented as mean + NSD. For each treatment, three to six culture wells were used, and each experiment was repeated four to five times. Data were compared by analysis of variance.
|
ACKNOWLEDGEMENTS |
|---|
We thank Paul McHugh and the Department of Psychiatry of Johns Hopkins University School of Medicine for support. This work was supported by USPHS NIH/NINDS grant NS38377. T.M.D. and V.L.D. are supported by the Edward O. and Mitchell Family Foundation. Y.T. was supported by the Welfide Medicinal Research Foundation (Japan).
|
FOOTNOTES |
|---|
+ To whom correspondence should be addressed at: Department of Psychiatry, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Room 618, Baltimore, MD 21205-2196, USA. Tel: +1 410 614 0011; Fax: +1 410 614 0013; Email: caross@jhu.edu
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
1 Forno, L.S. (1996) Neuropathology of Parkinson’s disease. J. Neuropathol. Exp. Neurol., 55, 259–272.[Web of Science][Medline]
2 Hardy, J. and Gwinn-Hardy, K. (1998) Genetic classification of primary neurodegenerative disease. Science, 282, 1075–1079.
3 Gibb, W.R. and Lees, A.J. (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry, 51, 745–752.
4 Olanow, C.W. and Tatton, W.G. (1999) Etiology and pathogenesis of Parkinson’s disease. Annu. Rev. Neurosci., 22, 123–144.[Web of Science][Medline]
5 Dunnett, S.B. and Bjorklund, A. (1999) Prospects for new restorative and neuroprotective treatments in Parkinson’s disease. Nature, 399, A32–A39.[Medline]
6 Polymeropoulos, M.H., Lavedan, C., Leroy, E., Ide, S.E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R. et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science, 276, 2045–2047.
7 Kruger, R., Kuhn, W., Muller, T., Woitalla, D., Graeber, M., Kosel, S., Przuntek, H., Epplen, J.T., Schols, L. and Riess, O. (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nature Genet., 18, 106–108.[Web of Science][Medline]
8 Spillantini, M.G., Schmidt, M.L., Lee, V.M., Trojanowski, J.Q., Jakes, R. and Goedert, M. (1997) Alpha-synuclein in Lewy bodies. Nature, 388, 839–840.[Medline]
9 Spillantini, M.G., Crowther, R.A., Jakes, R., Hasegawa, M. and Goedert, M. (1998) Alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc. Natl Acad. Sci. USA, 95, 6469–6473.
10 Baba, M., Nakajo, S., Tu, P.H., Tomita, T., Nakaya, K., Lee, V.M., Trojanowski, J.Q. and Iwatsubo, T. (1998) Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am. J. Pathol., 152, 879–884.[Abstract]
11 Masliah, E., Rockenstein, E., Veinbergs, I., Mallory, M., Hashimoto, M., Takeda, A., Sagara, Y., Sisk, A. and Mucke, L. (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science, 287, 1265–1269.
12 Feany, M.B. and Bender, W.W. (2000) A Drosophila model of Parkinson’s disease. Nature, 404, 394–398.[Medline]
13 van der Putten, H., Wiederhold, K.H., Probst, A., Barbieri, S., Mistl, C., Danner, S., Kauffmann, S., Hofele, K., Spooren, W.P., Ruegg, M.A. et al. (2000) Neuropathology in mice expressing human alpha-synuclein. J. Neurosci., 20, 6021–6029.
14 Kahle, P.J., Neumann, M., Ozmen, L., Muller, V., Jacobsen, H., Schindzielorz, A., Okochi, M., Leimer, U., van Der Putten, H., Probst, A. et al. (2000) Subcellular localization of wild-type and Parkinson’s disease-associated mutant alpha-synuclein in human and transgenic mouse brain. J. Neurosci., 20, 6365–6373.
15 Ii, K., Ito, H., Tanaka, K. and Hirano, A. (1997) Immunocytochemical co-localization of the proteasome in ubiquitinated structures in neurodegenerative diseases and the elderly. J. Neuropathol. Exp. Neurol., 56, 125–131.[Web of Science][Medline]
16 Shimura, H., Hattori, N., Kubo, S., Mizuno, Y., Asakawa, S., Minoshima, S., Shimizu, N., Iwai, K., Chiba, T., Tanaka, K. et al. (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nature Genet., 25, 302–305.[Web of Science][Medline]
17 Zhang, Y., Gao, J., Chung, K.K., Huang, H., Dawson, V.L. and Dawson, T.M. (2000) 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, 97, 13354–13359.
18 Imai, Y., Soda, M. and Takahashi, R. (2000) Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J. Biol. Chem., 275, 35661–35664.
19 Leroy, E., Boyer, R., Auburger, G., Leube, B., Ulm, G., Mezey, E., Harta, G., Brownstein, M.J., Jonnalagada, S., Chernova, T. et al. (1998) The ubiquitin pathway in Parkinson’s disease. Nature, 395, 451–452.[Medline]
20 Larsen, C.N., Krantz, B.A. and Wilkinson, K.D. (1998) Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolases. Biochemistry, 37, 3358–3368.[Medline]
21 Swerdlow, R.H., Parks, J.K., Davis, J.N., II, Cassarino, D.S., Trimmer, P.A., Currie, L.J., Dougherty, J., Bridges, W.S., Bennett, J.P.,Jr, Wooten, G.F. et al. (1998) Matrilineal inheritance of complex I dysfunction in a multigenerational Parkinson’s disease family. Ann. Neurol., 44, 873–881.[Web of Science][Medline]
22 Mizuno, Y., Yoshino, H., Ikebe, S., Hattori, N., Kobayashi, T., Shimoda-Matsubayashi, S., Matsumine, H. and Kondo, T. (1998) Mitochondrial dysfunction in Parkinson’s disease. Ann. Neurol., 44, S99–S109.[Web of Science][Medline]
23 Schapira, A.H., Gu, M., Taanman, J.W., Tabrizi, S.J., Seaton, T., Cleeter, M. and Cooper, J.M. (1998) Mitochondria in the etiology and pathogenesis of Parkinson’s disease. Ann. Neurol., 44, S89–S98.[Web of Science][Medline]
24 Kroemer, G. and Reed, J.C. (2000) Mitochondrial control of cell death. Nat. Med., 6, 513–519.[Web of Science][Medline]
25 Zhang, Y., Dawson, V.L. and Dawson, T.M. (2000) Oxidative stress and genetics in the pathogenesis of Parkinson’s disease. Neurobiol. Dis., 7, 240–250.[Web of Science][Medline]
26 Langston, J.W., Ballard, P., Tetrud, J.W. and Irwin, I. (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science, 219, 979–980.
27 Nicklas, W.J., Vyas, I. and Heikkila, R.E. (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci., 36, 2503–2508.[Web of Science][Medline]
28 Tipton, K.F. and Singer, T.P. (1993) Advances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds. J. Neurochem., 61, 1191–1206.[Web of Science][Medline]
29 Hsu, L.J., Sagara, Y., Arroyo, A., Rockenstein, E., Sisk, A., Mallory, M., Wong, J., Takenouchi, T., Hashimoto, M. and Masliah, E. (2000) Alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am. J. Pathol., 157, 401–410.
30 Takashima, A. and Koike, T. (1985) Relationship between dopamine content and its secretion in PC12 cells as a function of cell growth. Biochim. Biophys. Acta, 847, 101–107.[Medline]
31 Fenteany, G. and Schreiber, S.L. (1998) Lactacystin, proteasome function, and cell fate. J. Biol. Chem., 273, 8545–8548.
32 Kroemer, G., Dallaporta, B. and Resche-Rigon, M. (1998) The mitochondrial death/life regulator in apoptosis and necrosis. Annu. Rev. Physiol., 60, 619–642.[Web of Science][Medline]
33 Sawa, A., Wiegand, G.W., Cooper, J., Margolis, R.L., Sharp, A.H., Lawler, J.F.,Jr, Greenamyre, J.T., Snyder, S.H. and Ross, C.A. (1999) Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization. Nat. Med., 5, 1194–1198.[Web of Science][Medline]
34 Nicolli, A., Basso, E., Petronilli, V., Wenger, R.M. and Bernardi, P. (1996) Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, and cyclosporin A-sensitive channel. J. Biol. Chem., 271, 2185–2192.
35 Marchetti, P., Castedo, M., Susin, S.A., Zamzami, N., Hirsch, T., Macho, A., Haeffner, A., Hirsch, F., Geuskens, M. and Kroemer, G. (1996) Mitochondrial permeability transition is a central coordinating event of apoptosis. J. Exp. Med., 184, 1155–1160.
36 Green, D.R. and Reed, J.C. (1998) Mitochondria and apoptosis. Science, 281, 1309–1312.
37 Ghee, M., Fournier, A. and Mallet, J. (2000) Rat alpha-synuclein interacts with tat binding protein 1, a component of the 26S proteasomal complex. J. Neurochem., 75, 2221–2224.[Web of Science][Medline]
38 Saigoh, K., Wang, Y.L., Suh, J.G., Yamanishi, T., Sakai, Y., Kiyosawa, H., Harada, T., Ichihara, N., Wakana, S., Kikuchi, T. et al. (1999) Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice. Nature Genet., 23, 47–51.[Web of Science][Medline]
39 McNaught, K.S. and Jenner, P. (2001) Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci. Lett., 297, 191–194.[Web of Science][Medline]
40 Tabrizi, S.J., Orth, M., Wilkinson, J.M., Taanman, J.W., Warner, T.T., Cooper, J.M. and Schapira, A.H. (2000) Expression of mutant alpha-synuclein causes increased susceptibility to dopamine toxicity. Hum. Mol. Genet., 9, 2683–2689.
41 Scheffner, M., Huibregtse, J.M., Vierstra, R.D. and Howley, P.M. (1993) The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell, 75, 495–505.[Web of Science][Medline]
42 Palombella, V.J., Rando, O.J., Goldberg, A.L. and Maniatis, T. (1994) The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell, 78, 773–785.[Web of Science][Medline]
43 Chang, Y.C., Lee, Y.S., Tejima, T., Tanaka, K., Omura, S., Heintz, N.H., Mitsui, Y. and Magae, J. (1998) mdm2 and bax, downstream mediators of the p53 response, are degraded by the ubiquitin-proteasome pathway. Cell Growth Differ., 9, 79–84.[Abstract]
44 Liu, X., Zou, H., Slaughter, C. and Wang, X. (1997) DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell, 89, 175–184.[Web of Science][Medline]
45 Enari, M., Sakahira, H., Yokoyama, H., Okawa, K., Iwamatsu, A. and Nagata, S. (1998) A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature, 391, 43–50.[Medline]
46 Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S.M., Ahmad, M., Alnemri, E.S. and Wang, X. (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell, 91, 479–489.[Web of Science][Medline]
47 Kuida, K., Haydar, T.F., Kuan, C.Y., Gu, Y., Taya, C., Karasuyama, H., Su, M.S., Rakic, P. and Flavell, R.A. (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell, 94, 325–337.[Web of Science][Medline]
48 Nagata, S. (1997) Apoptosis by death factor. Cell, 88, 355–365.[Web of Science][Medline]
49 Muzio, M., Stockwell, B.R., Stennicke, H.R., Salvesen, G.S. and Dixit, V.M. (1998) An induced proximity model for caspase-8 activation. J. Biol. Chem., 273, 2926–2930.
50 Yang, X., Chang, H.Y. and Baltimore, D. (1998) Autoproteolytic activation of pro-caspases by oligomerization. Mol. Cell., 1, 319–325.[Web of Science][Medline]
51 Cassarino, D.S., Swerdlow, R.H., Parks, J.K., Parker, W.D.,Jr and Bennett, J.P.,Jr. (1998) Cyclosporin A increases resting mitochondrial membrane potential in SY5Y cells and reverses the depressed mitochondrial membrane potential of Alzheimer’s disease cybrids. Biochem. Biophys. Res. Commun., 248, 168–173.[Web of Science][Medline]
52 Guo, Q., Fu, W., Holtsberg, F.W., Steiner, S.M. and Mattson, M.P. (1999) Superoxide mediates the cell-death-enhancing action of presenilin-1 mutations. J. Neurosci. Res., 56, 457–470.[Web of Science][Medline]
53 Passer, B.J., Pellegrini, L., Vito, P., Ganjei, J.K. and D’Adamio, L. (1999) Interaction of Alzheimer’s presenilin-1 and presenilin-2 with Bcl-X(L). A potential role in modulating the threshold of cell death. J. Biol. Chem., 274, 24007–24013.
54 Cooper, J.M. and Schapira, A.H. (1997) Mitochondrial dysfunction in neurodegeneration. J. Bioenerg. Biomembr., 29, 175–183.[Web of Science][Medline]
55 Mochizuki, H., Goto, K., Mori, H. and Mizuno, Y. (1996) Histochemical detection of apoptosis in Parkinson’s disease. J. Neurol. Sci., 137, 120–123.[Web of Science][Medline]
56 Offen, D., Ziv, I., Sternin, H., Melamed, E. and Hochman, A. (1996) Prevention of dopamine-induced cell death by thiol antioxidants: possible implications for treatment of Parkinson’s disease. Exp. Neurol., 141, 32–39.[Web of Science][Medline]
57 Ziv, I., Barzilai, A., Offen, D., Nardi, N. and Melamed, E. (1997) Nigrostriatal neuronal death in Parkinson’s disease—a passive or an active genetically-controlled process? J. Neural Transm., 49 (suppl.), 69–76.
58 Tompkins, M.M., Basgall, E.J., Zamrini, E. and Hill, W.D. (1997) Apoptotic-like changes in Lewy-body-associated disorders and normal aging in substantia nigral neurons. Am. J. Pathol., 150, 119–131.[Abstract]
59 Tatton, N.A. and Kish, S.J. (1997) In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining. Neuroscience, 77, 1037–1048.[Web of Science][Medline]
60 Ruberg, M., France-Lanord, V., Brugg, B., Lambeng, N., Michel, P.P., Anglade, P., Hunot, S., Damier, P., Faucheux, B., Hirsch, E. et al. (1997). Rev. Neurol., 153, 499–508.[Medline]
61 Fall, C.P. and Bennett, J.P. (1999) Characterization and time course of MPP+ -induced apoptosis in human SH-SY5Y neuroblastoma cells. J. Neurosci. Res., 55, 620–628.[Web of Science][Medline]
62 Ostrerova, N., Petrucelli, L., Farrer, M., Mehta, N., Choi, P., Hardy, J. and Wolozin, B. (1999) -Synuclein shares physical and functional homology with 14-3-3 proteins. J. Neurosci., 19, 5782–5791.
63 Ostrerova-Golts, N., Petrucelli, L., Hardy, J., Lee, J.M., Farer, M. and Wolozin, B. (2000) The A53T -synuclein mutation increases iron-dependent aggregation and toxicity. J. Neurosci., 20, 6048–6054.
64 Keller, J.N., Huang, F.F., Dimayuga, E.R. and Maragos, W.F. (2000) Dopamine induces proteasome inhibition in neural PC12 cell line. Free Radic. Biol. Med., 29, 1037–1042.[Web of Science][Medline]
65 Ankarcrona, M., Dypbukt, J.M., Bonfoco, E., Zhivotovsky, B., Orrenius, S., Lipton, S.A. and Nicotera, P. (1995) Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron, 15, 961–973.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. Szargel, R. Rott, A. Eyal, J. Haskin, V. Shani, L. Balan, H. Wolosker, and S. Engelender Synphilin-1A Inhibits Seven in Absentia Homolog (SIAH) and Modulates {alpha}-Synuclein Monoubiquitylation and Inclusion Formation J. Biol. Chem., April 24, 2009; 284(17): 11706 - 11716. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. K. Tsang, Y.-I. Lee, H. S. Ko, J. M. Savitt, O. Pletnikova, J. C. Troncoso, V. L. Dawson, T. M. Dawson, and K. K. K. Chung S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease PNAS, March 24, 2009; 106(12): 4900 - 4905. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Azeredo da Silveira, B. L. Schneider, C. Cifuentes-Diaz, D. Sage, T. Abbas-Terki, T. Iwatsubo, M. Unser, and P. Aebischer Phosphorylation does not prompt, nor prevent, the formation of {alpha}-synuclein toxic species in a rat model of Parkinson's disease Hum. Mol. Genet., March 1, 2009; 18(5): 872 - 887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sugeno, A. Takeda, T. Hasegawa, M. Kobayashi, A. Kikuchi, F. Mori, K. Wakabayashi, and Y. Itoyama Serine 129 Phosphorylation of {alpha}-Synuclein Induces Unfolded Protein Response-mediated Cell Death J. Biol. Chem., August 22, 2008; 283(34): 23179 - 23188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N.-Y. Zhang, Z. Tang, and C.-W. Liu {alpha}-Synuclein Protofibrils Inhibit 26 S Proteasome-mediated Protein Degradation: UNDERSTANDING THE CYTOTOXICITY OF PROTEIN PROTOFIBRILS IN NEURODEGENERATIVE DISEASE PATHOGENESIS J. Biol. Chem., July 18, 2008; 283(29): 20288 - 20298. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kostka, T. Hogen, K. M. Danzer, J. Levin, M. Habeck, A. Wirth, R. Wagner, C. G. Glabe, S. Finger, U. Heinzelmann, et al. Single Particle Characterization of Iron-induced Pore-forming {alpha}-Synuclein Oligomers J. Biol. Chem., April 18, 2008; 283(16): 10992 - 11003. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Casas, R. Gomis, F. M. Gribble, J. Altirriba, S. Knuutila, and A. Novials Impairment of the Ubiquitin-Proteasome Pathway Is a Downstream Endoplasmic Reticulum Stress Response Induced by Extracellular Human Islet Amyloid Polypeptide and Contributes to Pancreatic {beta}-Cell Apoptosis Diabetes, September 1, 2007; 56(9): 2284 - 2294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. R. Flower, C. Clark-Dixon, C. Metoyer, H. Yang, R. Shi, Z. Zhang, and S. N. Witt YGR198w (YPP1) targets A30P {alpha}-synuclein to the vacuole for degradation J. Cell Biol., July 30, 2007; 177(6): 1091 - 1104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fujita, S. Sugama, M. Nakai, T. Takenouchi, J. Wei, T. Urano, S. Inoue, and M. Hashimoto {alpha}-Synuclein Stimulates Differentiation of Osteosarcoma Cells: RELEVANCE TO DOWN-REGULATION OF PROTEASOME ACTIVITY J. Biol. Chem., February 23, 2007; 282(8): 5736 - 5748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. V. Mosharov, R. G. W. Staal, J. Bove, D. Prou, A. Hananiya, D. Markov, N. Poulsen, K. E. Larsen, C. M. H. Moore, M. D. Troyer, et al. {alpha}-Synuclein Overexpression Increases Cytosolic Catecholamine Concentration J. Neurosci., September 6, 2006; 26(36): 9304 - 9311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. St. P. McNaught, T. Jackson, R. JnoBaptiste, A. Kapustin, and C. W. Olanow Proteasomal dysfunction in sporadic Parkinson's disease Neurology, May 23, 2006; 66(10_suppl_4): S37 - S49. [Abstract] [Full Text]
|
|
|
|
|
|
C. W. Shults Lewy bodies PNAS, February 7, 2006; 103(6): 1661 - 1668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Avraham, R. Szargel, A. Eyal, R. Rott, and S. Engelender Glycogen Synthase Kinase 3beta Modulates Synphilin-1 Ubiquitylation and Cellular Inclusion Formation by SIAH: IMPLICATIONS FOR PROTEASOMAL FUNCTION AND LEWY BODY FORMATION J. Biol. Chem., December 30, 2005; 280(52): 42877 - 42886. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. W. Smith, H. Jiang, Z. Pei, Y. Tanaka, H. Morita, A. Sawa, V. L. Dawson, T. M. Dawson, and C. A. Ross Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity Hum. Mol. Genet., December 15, 2005; 14(24): 3801 - 3811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Silvestri, V. Caputo, E. Bellacchio, L. Atorino, B. Dallapiccola, E. M. Valente, and G. Casari Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism Hum. Mol. Genet., November 15, 2005; 14(22): 3477 - 3492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. W. Bertoncini, C. O. Fernandez, C. Griesinger, T. M. Jovin, and M. Zweckstetter Familial Mutants of {alpha}-Synuclein with Increased Neurotoxicity Have a Destabilized Conformation J. Biol. Chem., September 2, 2005; 280(35): 30649 - 30652. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Chen, J. Thorpe, and J. N. Keller {alpha}-Synuclein Alters Proteasome Function, Protein Synthesis, and Stationary Phase Viability J. Biol. Chem., August 26, 2005; 280(34): 30009 - 30017. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhang, M. Shimoji, B. Thomas, D. J. Moore, S.-W. Yu, N. I. Marupudi, R. Torp, I. A. Torgner, O. P. Ottersen, T. M. Dawson, et al. Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis Hum. Mol. Genet., July 15, 2005; 14(14): 2063 - 2073. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Y. Chung, H. Seo, K. C. Sonntag, A. Brooks, L. Lin, and O. Isacson Cell type-specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection Hum. Mol. Genet., July 1, 2005; 14(13): 1709 - 1725. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. W. Smith, R. L. Margolis, X. Li, J. C. Troncoso, M. K. Lee, V. L. Dawson, T. M. Dawson, T. Iwatsubo, and C. A. Ross {alpha}-Synuclein Phosphorylation Enhances Eosinophilic Cytoplasmic Inclusion Formation in SH-SY5Y Cells J. Neurosci., June 8, 2005; 25(23): 5544 - 5552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Dixon, N. Mathias, R. M. Zweig, D. A. Davis, and D. S. Gross {alpha}-Synuclein Targets the Plasma Membrane via the Secretory Pathway and Induces Toxicity in Yeast Genetics, May 1, 2005; 170(1): 47 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Zhang, T. Wang, Z. Pei, D. S. Miller, X. Wu, M. L. Block, B. Wilson, W. Zhang, Y. Zhou, J.-S. Hong, et al. Aggregated {alpha}-synuclein activates microglia: a process leading to disease progression in Parkinson's disease FASEB J, April 1, 2005; 19(6): 533 - 542. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Snyder, K. Mensah, C. Hsu, M. Hashimoto, I. G. Surgucheva, B. Festoff, A. Surguchov, E. Masliah, A. Matouschek, and B. Wolozin {beta}-Synuclein Reduces Proteasomal Inhibition by {alpha}-Synuclein but Not {gamma}-Synuclein J. Biol. Chem., March 4, 2005; 280(9): 7562 - 7569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Martin-Clemente, B. Alvarez-Castelao, I. Mayo, A. B. Sierra, V. Diaz, M. Milan, I. Farinas, T. Gomez-Isla, I. Ferrer, and J. G. Castano {alpha}-Synuclein Expression Levels Do Not Significantly Affect Proteasome Function and Expression in Mice and Stably Transfected PC12 Cell Lines J. Biol. Chem., December 17, 2004; 279(51): 52984 - 52990. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. J. Rideout, P. Dietrich, Q. Wang, W. T. Dauer, and L. Stefanis {alpha}-Synuclein Is Required for the Fibrillar Nature of Ubiquitinated Inclusions Induced by Proteasomal Inhibition in Primary Neurons J. Biol. Chem., November 5, 2004; 279(45): 46915 - 46920. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Li, C. Lesuisse, Y. Xu, J. C. Troncoso, D. L. Price, and M. K. Lee Stabilization of {alpha}-Synuclein Protein with Aging and Familial Parkinson's Disease-Linked A53T Mutation J. Neurosci., August 18, 2004; 24(33): 7400 - 7409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Lindersson, R. Beedholm, P. Hojrup, T. Moos, W. Gai, K. B. Hendil, and P. H. Jensen Proteasomal Inhibition by {alpha}-Synuclein Filaments and Oligomers J. Biol. Chem., March 26, 2004; 279(13): 12924 - 12934. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Tanaka, Y. M. Kim, G. Lee, E. Junn, T. Iwatsubo, and M. M. Mouradian Aggresomes Formed by {alpha}-Synuclein and Synphilin-1 Are Cytoprotective J. Biol. Chem., February 6, 2004; 279(6): 4625 - 4631. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Baptista, M. R. Cookson, and D. W. Miller Parkin and {alpha}-Synuclein: Opponent Actions in The Pathogenesis of Parkinson'S Disease Neuroscientist, February 1, 2004; 10(1): 63 - 72. [Abstract] [PDF]
|
|
|
|
 |
|
 N. Ninkina, K. Papachroni, D. C. Robertson, O. Schmidt, L. Delaney, F. O'Neill, F. Court, A. Rosenthal, S. M. Fleetwood-Walker, A. M. Davies, et al. Neurons Expressing the Highest Levels of {gamma}-Synuclein Are Unaffected by Targeted Inactivation of the Gene Mol. Cell. Biol., November 15, 2003; 23(22): 8233 - 8245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Ardley, G. B. Scott, S. A. Rose, N. G. S. Tan, A. F. Markham, and P. A. Robinson Inhibition of Proteasomal Activity Causes Inclusion Formation in Neuronal and Non-Neuronal Cells Overexpressing Parkin Mol. Biol. Cell, November 1, 2003; 14(11): 4541 - 4556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Dawson and V. L. Dawson Molecular Pathways of Neurodegeneration in Parkinson's Disease Science, October 31, 2003; 302(5646): 819 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Iwata, M. Maruyama, T. Akagi, T. Hashikawa, I. Kanazawa, S. Tsuji, and N. Nukina Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies Hum. Mol. Genet., October 16, 2003; 12(20): 2625 - 2635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. C. Tsai, P. S. Fishman, N. V. Thakor, and G. A. Oyler Parkin Facilitates the Elimination of Expanded Polyglutamine Proteins and Leads to Preservation of Proteasome Function J. Biol. Chem., June 6, 2003; 278(24): 22044 - 22055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Snyder, K. Mensah, C. Theisler, J. Lee, A. Matouschek, and B. Wolozin Aggregated and Monomeric alpha -Synuclein Bind to the S6' Proteasomal Protein and Inhibit Proteasomal Function J. Biol. Chem., March 28, 2003; 278(14): 11753 - 11759. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Darios, O. Corti, C. B. Lucking, C. Hampe, M.-P. Muriel, N. Abbas, W.-J. Gu, E. C. Hirsch, T. Rooney, M. Ruberg, et al. Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death Hum. Mol. Genet., March 1, 2003; 12(5): 517 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. J. Rideout, Q. Wang, D. S. Park, and L. Stefanis Cyclin-Dependent Kinase Activity Is Required for Apoptotic Death But Not Inclusion Formation in Cortical Neurons after Proteasomal Inhibition J. Neurosci., February 15, 2003; 23(4): 1237 - 1245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Allen, P. R. Heath, J. Kirby, S. B. Wharton, M. R. Cookson, F. M. Menzies, R. E. Banks, and P. J. Shaw Analysis of the Cytosolic Proteome in a Cell Culture Model of Familial Amyotrophic Lateral Sclerosis Reveals Alterations to the Proteasome, Antioxidant Defenses, and Nitric Oxide Synthetic Pathways J. Biol. Chem., February 14, 2003; 278(8): 6371 - 6383. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Ryu, H. P. Harding, J. M. Angelastro, O. V. Vitolo, D. Ron, and L. A. Greene Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cellular Models of Parkinson's Disease J. Neurosci., December 15, 2002; 22(24): 10690 - 10698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Junn, S. S. Lee, U. T. Suhr, and M. M. Mouradian Parkin Accumulation in Aggresomes Due to Proteasome Impairment J. Biol. Chem., November 27, 2002; 277(49): 47870 - 47877. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-Z. Pan, W. Bruening, B. I. Giasson, V. M.-Y. Lee, and A. K. Godwin gamma -Synuclein Promotes Cancer Cell Survival and Inhibits Stress- and Chemotherapy Drug-induced Apoptosis by Modulating MAPK Pathways J. Biol. Chem., September 13, 2002; 277(38): 35050 - 35060. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Mattson, S. L. Chan, and W. Duan Modification of Brain Aging and Neurodegenerative Disorders by Genes, Diet, and Behavior Physiol Rev, July 1, 2002; 82(3): 637 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Ding, J. J. Lewis, K. M. Strum, E. Dimayuga, A. J. Bruce-Keller, J. C. Dunn, and J. N. Keller Polyglutamine Expansion, Protein Aggregation, Proteasome Activity, and Neural Survival J. Biol. Chem., April 12, 2002; 277(16): 13935 - 13942. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. H. V. Schapira Neuroprotection and dopamine agonists Neurology, February 1, 2002; 58(90001): S9 - 18. [Abstract] [Full Text]
|
|
|
|
|
|
M. M. Mouradian Recent advances in the genetics and pathogenesis of Parkinson disease Neurology, January 22, 2002; 58(2): 179 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Stefanis, K. E. Larsen, H. J. Rideout, D. Sulzer, and L. A. Greene Expression of A53T Mutant But Not Wild-Type alpha -Synuclein in PC12 Cells Induces Alterations of the Ubiquitin-Dependent Degradation System, Loss of Dopamine Release, and Autophagic Cell Death J. Neurosci., December 15, 2001; 21(24): 9549 - 9560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Matilla, C. Gorbea, D. D. Einum, J. Townsend, A. Michalik, C. van Broeckhoven, C. C. Jensen, K. J. Murphy, L. J. Ptacek, and Y.-H. Fu Association of ataxin-7 with the proteasome subunit S4 of the 19S regulatory complex Hum. Mol. Genet., November 1, 2001; 10(24): 2821 - 2831. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Paxinou, Q. Chen, M. Weisse, B. I. Giasson, E. H. Norris, S. M. Rueter, J. Q. Trojanowski, V. M.-Y. Lee, and H. Ischiropoulos Induction of {alpha}-Synuclein Aggregation by Intracellular Nitrative Insult J. Neurosci., October 15, 2001; 21(20): 8053 - 8061. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||