The DOI matches its Crossref record; 27 of the 28 references it cites were found in a registry or an index.
Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy
Abstract
Aberrant α-synuclein degradation is implicated in Parkinson's disease pathogenesis because the protein accumulates in the Lewy inclusion bodies associated with the disease. Little is known, however, about the pathways by which wild-type α-synuclein is normally degraded. We found that wild-type α-synuclein was selectively translocated into lysosomes for degradation by the chaperone-mediated autophagy pathway. The pathogenic A53T and A30P α-synuclein mutants bound to the receptor for this pathway on the lysosomal membrane, but appeared to act as uptake blockers, inhibiting both their own degradation and that of other substrates. These findings may underlie the toxic gain-of-function by the mutants.
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In the citing paper
“Previous studies suggest that α-synuclein is degraded by macroautophagy, chaperone-mediated autophagy, and the proteasome20–23.”
From Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration (2020) · cites this paper as [20]
In the citing paper
“Finally, inhibition of a particular degradative pathway is typically accompanied by an increase in a separate pathway as the cell attempts to compensate for the loss of degradative capacity.158,478,493”
From Guidelines for the use and interpretation of assays for monitoring autophagy (2012) · cites this paper as [493]
In the citing paper
“and animal models with defective lysosomal exocytosis (VAMP7 mice) or defective lysosomal protease activity (Cathepsin D mutant mice) have mild to moderate demyelination.40–42”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [42]
In the citing paper
“dopamine-modified α-synuclein blocks chaperone-mediated autophagy [109,110], which induces abnormal intracellular accumulation α-synuclein in PD [120].”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [109]
In the citing paper
“Early evidence suggested roles for CMA and macroautophagy in degrading SNCA/α‐synuclein (Webb et al, 2003; Cuervo et al, 2004).”
From Autophagy in major human diseases (2021) · cites this paper as Cuervo et al, 2004
In the citing paper
“High expression of wild‐type SNCA/α‐synuclein, mutations or unwanted posttranslational modifications on this protein (such as formation of dopamine adducts) is toxic to CMA by preventing multimerization of LAMP2A and subsequent lysosomal internalization of cargo proteins (Cuervo et al, 2004; Martinez‐Vicente et al, 2008).”
From Autophagy in major human diseases (2021) · cites this paper as Cuervo et al, 2004
In the citing paper
“The protein catabolic pathways that regulate synuclein degradation have been discussed by multiple authors4,16,17, and the extent to which autophagy contributes to synuclein degradation depends on the presence of mutations18.”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [18]
Citations
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Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System
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Self-citationAutophagy: in sickness and in health
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Self-citationPeptide sequences that target cytosolic proteins for lysosomal proteolysis
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LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease
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BackgroundHsp70 molecular chaperones and Parkinson's disease
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Autophagy protects against aminochrome-induced cell death in substantia nigra-derived cell line.
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“The pathogenic A53T and A30P a-synuclein mutants inhibit their own degradation and that of other substrates (Cuervo et al., 2004).”
BackgroundUbiquitin receptors and protein quality control
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“Likewise, chaperone-mediated autophagy is known to be impaired by DA-o-quinones (Cuervo et al. 2004).”
BackgroundImpaired protein degradation in FTLD and related disorders
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“…of such pathologic protein aggregates reduces the efficiency of the two major protein degradation systems, UPS (Bence et al. 2001, Bennett et al. 2005, Emmanouilidou et al. 2010, Jana et al. 2001) and the autophagy-lysosome system (Cuervo et al. 2004, Wang et al. 2009, Winslow et al. 2010).”
BackgroundInterplay between α-synuclein amyloid formation and membrane structure
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“Chaperonemediated autophagy (CMA) has been proposed as a degradation pathway for a-synuclein (Cuervo et al., 2004).”
BackgroundZhang, S., Eitan, E., Wu, T.-Y., & Mattson, M. P. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.09.016 · Cited by 76
“Normally, α-synuclein is degraded in proteasomes and by autophagy in lysosomes (Cuervo et al., 2004; Mak et al., 2010; Snyder et al., 2003; Webb et al., 2003; Xilouri et al., 2013).”
BackgroundZhang, J., Culp, M. L., Craver, J., & Darley-Usmar, V. M. (2018) · Journal of Neurochemistry · doi:10.1111/jnc.14308 · Cited by 74
“As a-synuclein, PARK7/DJ-1 accumulates in PD brains (Choi et al. 2006), and can be a substrate of chaperone-mediated autophagy (Cuervo et al. 2004; Wang et al. 2016).”
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Neuronal Autophagy in Synaptic Functions and Psychiatric Disorders
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The relationship of alpha-synuclein to mitochondrial dynamics and quality control
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Membrane trafficking in neuronal maintenance and degeneration
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“This pathological mechanism potentially clogs up the lysosomal system which also causes degradation problems for other proteins [156, 158].”
BackgroundUbiquitin–proteasome system dysfunction in Parkinson’s disease: current evidence and controversies
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Mutations in LRRK2 potentiate age-related impairment of autophagic flux
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“α-Synuclein has been shown to interact with the cell mediated autophagy pathway through a process that is inhibited by mutant A53T α-synuclein [12].”
BackgroundRegulation of autophagy by polyphenols: Paving the road for treatment of neurodegeneration
Nabavi, S. F., Sureda, A., Dehpour, A. R., Shirooie, S., Sanches-Silva, A. T., Devi, K. P., Ahmed, T., Ishaq, N., Hashim, R., Sobarzo‐Sánchez, E., et al. (2017) · Biotechnology Advances · doi:10.1016/j.biotechadv.2017.12.001 · Cited by 74
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“[1 27 ] TH + SN n eu ro d eg en er at io n ,”
BackgroundInfluentialParkinson's disease: acid‐glucocerebrosidase activity and alpha‐synuclein clearance
Blanz, J., & Säftig, P. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13517 · Cited by 75
“It is hypothesized that the pathogenic a-SN mutants (A53T and A30P) (Cuervo et al. 2004) as well as dopaminemodified a-SN (Martinez-Vicente et al. 2008) block lysosomal translocation, impairing their own degradation along with that of other CMA substrates (Cuervo et al. 2004).”
BackgroundArylsulfatase A, a genetic modifier of Parkinson’s disease, is an α-synuclein chaperone
Lee, J. S., Kanai, K., Suzuki, M., Kim, W. S., Yoo, H. S., Fu, Y., Kim, D.-K., Jung, B. C., Choi, M.-S., Oh, K. W., et al. (2019) · Brain · doi:10.1093/brain/awz205 · Cited by 69
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Malkus, K. A., & Ischiropoulos, H. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.03.017 · Cited by 71
“However, it remains unclear how dysfunction of protein degradation contributes to the regionally and temporally selective aggregation of α-syn. α-Syn has been shown to be preferentially degraded by CMA in vitro (Cuervo et al., 2004).”
BackgroundAnandhan, A., Rodríguez‐Rocha, H., Bohovych, I., Griggs, A. M., Zavala-Flores, L. M., Reyes‐Reyes, E. M., Seravalli, J., Stanciu, L., Lee, J., Rochet, J., et al. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.11.018 · Cited by 73
“Both autophagy and CMA have been reported to mediate the clearance of αsynuclein (Cuervo et al., 2004; Malkus and Ischiropoulos, 2012; Vogiatzi et al., 2008).”
Song, W., Patel, A., Qureshi, H. Y., Han, D., Schipper, H. M., & Paudel, H. K. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06165.x · Cited by 72
“Of note, inhibition of the proteosome may itself trigger autophagy (Cuervo et al. 2004; Pandey et al. 2007), and HO-1 overexpression has recently been shown to activate macroautophagy in astroglia (Zukor et al. 2009).”
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Targeting the Autophagy/Lysosomal Degradation Pathway in Parkinsons Disease
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Stress-Induced Cellular Clearance Is Mediated by the SNARE Protein ykt6 and Disrupted by α-Synuclein
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Self-citationThe multi‐faceted role of mitochondria in the pathology of Parkinson’s disease
Trinh, D., Israwi, A. R., Arathoon, L. R., Gleave, J. A., & Nash, J. E. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15154 · Cited by 74
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Alpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson’s Disease
Saramowicz, K., Siwecka, N., Galita, G., Kucharska-Lusina, A., Rozpędek‐Kamińska, W., & Majsterek, I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010360 · Cited by 79
“Recognized proteins are in turn targeted and delivered to the lysosome by the lysosomal-associated membrane protein 2A (LAMP2A) [175].”
Molecular Mechanisms of Pathogenesis of Parkinson's Disease
Shadrina, M. I., Slominsky, P. A., & Sa, L. (2010) · International review of cytology · doi:10.1016/s1937-6448(10)81006-8 · Cited by 70
“It was also shown that a mutant a-synuclein was mainly bound to lysosomal membrane receptors, thereby blocking both its own lysosome autophagia-induced degradation and the degradation of other protein substrates (Cuervo et al., 2004).”
BackgroundFeng, L., Federoff, H. J., Vicini, S., & Maguire‐Zeiss, K. A. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07266.x · Cited by 72
“…permeability (Betarbet et al., 2000; Sharon et al., 2001; Volles et al., 2001; Gosavi et al., 2002; Lee et al., 2002; Hashimoto et al., 2003; Cuervo et al., 2004; Rochet et al., 2004; Fornai et al., 2005; Furukawa et al., 2006; Martin et al., 2006; Bellucci et al., 2008; Borland et al.,…”
BackgroundCartier, A. E., Ubhi, K. K., Spencer, B. J., Vázquez‐Roque, R. A., Kosberg, K. A., Fourgeaud, L., Kanayson, P., Patrick, C., Rockenstein, E. M., Patrick, G. N., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034713 · Cited by 71
Molecular control of chaperone-mediated autophagy
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Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, J., Abeliovich, H., Acevedo‐Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Kölner Universitäts PublikationsServer (Universität zu Köln) · doi:10.5167/uzh-131237 · Cited by 69
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Glucocerebrosidase Mutations alter the endoplasmic reticulum and lysosomes in Lewy body disease
Kurzawa‐Akanbi, M., Hanson, P. S., Blain, P. G., Lett, D. J., McKeith, I. G., Chinnery, P. F., & Morris, C. M. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07879.x · Cited by 71
“It is plausible that mutant glucocerebrosidase interferes with cellular clearance of a-synuclein via lysosomal pathway and stimulates protein aggregation (Cuervo et al. 2004; Mazzulli et al. 2011), thus predisposing to the development of synucleinopathies.”
Accumulation and clearance of α‐synuclein aggregates demonstrated by time‐lapse imaging
Opazo, F., Krenz, A., Heermann, S., Schulz, J. B., & Falkenburger, B. H. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05407.x · Cited by 71
“This finding would be in line with previous reports of impaired degradation pathways by A53T but not WT-a-synuclein (Stefanis et al. 2001; Cuervo et al. 2004; Jiang et al. 2006).”
BackgroundResultChoi, H. S., An, J. J., Kim, S. Y., Lee, S. H., Kim, D. W., Yoo, K., Won, M. H., Kang, T., Kwon, H. J., Kang, J. H., et al. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.06.006 · Cited by 69
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“During the aging process, deficits in autophagy have been described in Alzheimer’s disease (AD; Nixon et al. 2005; Pickford et al. 2008), Parkinson’s disease (PD; Crews et al. 2010; Cuervo et al. 2004), and other aging-related disorders (Cuervo 2004).”
BackgroundClioquinol induces autophagy in cultured astrocytes and neurons by acting as a zinc ionophore
Park, M.-H., Lee, S.-J., Byun, H.-R., Kim, Y., Oh, Y. J., Koh, J., & Hwang, J. J. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.01.009 · Cited by 70
“A number of neurodegenerative diseases are associated with accumulation of abnormal protein aggregates (Ross and Poirier, 2004), suggesting an important role for aberrant autophagy in their pathogenesis (Cuervo et al., 2004; Ravikumar et al., 2002; Ravikumar et al., 2004;Webb et al., 2003).”
BackgroundWenhua, B., Gu, Y., Ta, L., Wang, K., & Xu, Z. (2015) · Molecular Medicine Reports · doi:10.3892/mmr.2015.4599 · Cited by 69
Lysosomal alterations in peripheral blood mononuclear cells of Parkinson's disease patients
Papagiannakis, N., Xilouri, M., Koros, C., Stamelou, M., Antonelou, R. C., Maniati, M., Papadimitriou, D. A., Moraitou, M., Michelakakis, H., & Stefanis, L. (2015) · Movement Disorders · doi:10.1002/mds.26433 · Cited by 69
Self-citationProteolysis of α‐synuclein fibrils in the lysosomal pathway limits induction of inclusion pathology
Sacino, A. N., Brooks, M., Chakrabarty, P., Saha, K., Khoshbouei, H., Golde, T. E., & Giasson, B. I. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13743 · Cited by 71
“Interestingly, the major mechanisms involved in the cytoplasmic degradation of endogenous aS, macroautophagy, and chaperone-mediated autophagy, also require lysosome activity (Paxinou et al. 2001; Webb et al. 2003; Cuervo et al. 2004; Lee et al. 2004; Vogiatzi et al. 2008; Mak et al. 2010).”
BackgroundMechanism and Regulation of Autophagy and Its Role in Neuronal Diseases
Hu, Z., Yang, B., Mo, X., & Xiao, H. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8921-4 · Cited by 69
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“…(CMA), was observed in PD (Ravikumar et al., 2004; Nixon et al., 2005; Sarkar et al., 2007; Pan et al., 2008) and dementia with LBs (DLB), where a-Synuclein accumulation may alter autophagy and cause lysosomal dysfunction (Cuervo et al., 2004; Martinez-Vicente et al., 2008; Xilouri et al., 2009).”
Clues to how alpha‐synuclein damages neurons in Parkinson's disease
Sulzer, D. L. (2010) · Movement Disorders · doi:10.1002/mds.22639 · Cited by 68
Self-citationHu, X., Song, Q., Li, X., Li, D., Zhang, Q., Meng, W., & Zhao, Q. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.02.022 · Cited by 68
“Because the PD induced by misfolded a-synuclein could be cleared by autophagic pathway [Bandhyopadhyay and Cuervo, 2007], which supports the hypothesis that impairing the autophagic degradation will aggravate the progress of PD [Cuervo et al., 2004].”
BackgroundKeeling, E., Lotery, A. J., Tumbarello, D. A., & Ratnayaka, J. A. (2018) · Cells · doi:10.3390/cells7020016 · Cited by 72
The Role of Free Radicals in Autophagy Regulation: Implications for Ageing
Pajares, M. A., Cuadrado, A., Engedal, N., Jirsova, Z., & Cahová, M. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/2450748 · Cited by 69
“CMA Decline in Ageing.”
BackgroundInfluentialG2019S LRRK2 mutation facilitates α-synuclein neuropathology in aged mice
Novello, S., Arcuri, L., Doveró, S., Dutheil, N., Shimshek, D. R., Bézard, E., & Morari, M. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.08.018 · Cited by 70
Xilouri, M., & Stefanis, L. (2015) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2015.01.003 · Cited by 68
“Tight binding of the mutant forms was confirmed in a neuronal cell context, in the rat pheochromocytoma PC12 cell line (Cuervo et al. 2004).”
BackgroundInfluentialSelf-citationTsujimura, A., Taguchi, K., Watanabe, Y., Tatebe, H., Tokuda, T., Mizuno, T., & Tanaka, M. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.10.011 · Cited by 67
“On the other hand, CMA reportedly contributes to α-Syn monomer transfer to lysosomes and subsequent degradation (Cuervo et al., 2004; Xilouri et al., 2009).”
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“Autophagy and chaperone-mediated autophagy have been proposed to prevent α-synuclein accumulation (Cuervo et al., 2004; Webb et al., 2003), whereas Parkin and PTEN-induced putative kinase 1 have been shown to regulate mitochondrial targeted autophagy (mitophagy) (Dagda et al.”
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“Such strategies have the advantage that they would theoretically not only enhance excess a-Synuclein clearance, but also mitigate its aberrant effects on lysosomes, which have been observed in various cellular systems [46,48,57,58].”
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“…general protein turnover is maintained in cells under inhibition of chaperone-mediated autophagy by an upregulation of macroautophagy, this cannot confer protection against oxidative stress or aid in the degradation of the aggregation-prone mutant protein (Cuervo et al 2004; Massey et al 2006).”
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“Interestingly, recent studies have shown that the PD-linked α-synuclein A53T and A30P point mutants that rapidly form annular oligomers in vitro also bind strongly to lysosome vesicles and inhibit the chaperone-dependent autophagy pathway ( Cuervo et al., 2004 ).”
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“Both unfolded and aggregated might be neurotoxic via a variety of pathways including inhibition of protein degradation by chaperonemediated autophagy (Cuervo et al. 2004) and membrane permeabilization (Rochet et al. 2004; Mosharov et al. 2006; Staal et al. 2008).”
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“Others saw only a very small contribution of macroautophagy to the degradation of alpha-synuclein in cell culture, but the greatest contribution of chaperone-mediated-autophagy to the degradation of alpha-synuclein (Cuervo et al., 2004).”
Background
Metadata
- Authors
- Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T., & Sulzer, D.
- Affiliations
- Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
- Brigham and Women's Hospital (US)
- Venue
- Science
- Published
- 2004-08-27
- Volume
- 305
- Issue
- 5688
- Pages
- 1292-1295
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2068288454
- Cited by
- 2,024
- References
- 28
- Citations by year
- 2026: 64 · 2025: 77 · 2024: 102 · 2023: 71 · 2022: 107 · 2021: 114 · 2020: 128 · 2019: 114 · 2018: 117 · 2017: 101 · 2016: 95 · 2015: 92 · 2014: 93 · 2013: 108 · 2012: 119
- FWCI
- 34.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG-021904)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- alpha-synuclein, chaperone-mediated autophagy, Parkinson's disease, lysosomal degradation, A53T mutant, Lewy bodies, gain-of-function toxicity, protein degradation pathways
- MeSH terms
- Animals, Autophagy, Cells, Cultured, Glyceraldehyde-3-Phosphate Dehydrogenases, Half-Life, Intracellular Membranes, Lysosomes, Male, Mutation, Nerve Tissue Proteins, Neurons, Protein Binding, Antigens, CD, PC12 Cells, Rats, Wistar, Molecular Chaperones, Amino Acid Motifs, Protein Transport, Mice, Rats, Synucleins, alpha-Synuclein, Lysosomal Membrane Proteins
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