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]
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BackgroundInfluentialMolecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases
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BackgroundAlpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies
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BackgroundTherapeutics in the Pipeline Targeting α-Synuclein for Parkinson's Disease
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BackgroundInfluentialCurrent disease modifying approaches to treat Parkinson’s disease
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“In addition, both mutant α-synuclein and dopamine-modified α-synuclein and LRRK2 G2019S or LRRK2 R1441G mutants reduce the activity of CMA by binding to LAMP2A ( 24 , 27 , 45 , 46 ).”
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“…protein degradation pathway such as the ubiquitin–proteasomal system (UPS) (Rideout et al. 2001; Zhang et al. 2008) and chaperone- mediated autophagy (Cuervo et al. 2004). a-Synuclein is also involved in the virulent effects of the environmental toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine…”
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“GCase deficiency accelerates the accumulation of proteinase K-resistant Syn Since Syn has been reported to be degraded in lysosomes (13-15), we hypothesized that the loss of GCase activity compromises the Syn-degrading function of lysosomes, resulting in Syn accumulation.”
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“As such, it can protect against prostate cancer (PC) [14,15].”
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Self-citationThe Glucocerebrosidase Gene and Parkinson's Disease in Ashkenazi Jews
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“α-synuclein is linked with many pathways that can cause cell death, with roles in protein degradation and autophagy [34], endoplasmic reticulum stress [35], and histone acetylation [36].”
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Self-citationChaperone-mediated autophagy dysfunction in the pathogenesis of neurodegeneration
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“The first PD protein for which association to CMA was shown is α-synuclein (Cuervo et al., 2004).”
InfluentialSelf-citationAutophagy Is Increased in Postmortem Brains of Persons With HIV-1-Associated Encephalitis
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“In these conditions, an accumulation of autophagosomes is found in brains of persons who died of the disorders as well as in mouse models that represent an increase in autophagy associated with a deficiency in autophagosome-lysosome fusion [44–46].”
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Mitochondrial dysfunction associated with glucocerebrosidase deficiency
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“The accumulation of GlcCer in lysosomes of GD patients and thewell documented lysosomal dysfunction associated with PD (Alvarez-Erviti et al., 2010; Cuervo et al., 2004; Dehay et al., 2010), has meant that much of the GCase research in recent years has focused on the autophagy lysosome pathway…”
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Zucchelli, S., Codrich, M., Marcuzzi, F., Pinto, M., Vilotti, S., Biagioli, M., Ferrer, I., & Gustincich, S. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq290 · Cited by 99
Import and Export of Misfolded α-Synuclein
Rodriguez, L., Marano, M. M., & Tandon, A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00344 · Cited by 93
“Macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy direct intracellular constituents to the lysosome, and all of these processes could be involved in α-syn degradation.”
BackgroundInfluentialNeuroinflammation in Multiple System Atrophy: Response to and Cause of α-Synuclein Aggregation
Vieira, B. D. M., Radford, R. A., Chung, R. S., Guillemin, G. J., & Pountney, D. L. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00437 · Cited by 93
Mitochondrial Dysfunction in Genetic Animal Models of Parkinson's Disease
Trancikova, A. K., Tsika, E., & Moore, D. J. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4200 · Cited by 94
Genes associated with Parkinson's disease: regulation of autophagy and beyond
Beilina, A. G., & Cookson, M. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13266 · Cited by 98
“For example, Cuervo et al. (2004) found that a-synuclein is a substrate for the specialized form of autophagy, CMA.”
BackgroundChaperone‐mediated autophagy degrades Keap1 and promotes Nrf2‐mediated antioxidative response
Zhu, L., He, S., Huang, L. H., Ren, D., Nie, T., Tao, K. X., Li, X., Lu, F., Mao, Z., & Yang, Q. (2022) · Aging Cell · doi:10.1111/acel.13616 · Cited by 94
“And the activity of CMA declines with age, due to the reduction of the protein level of LAMP2A (the rating- limited factor of CMA), which induces or aggravates dysregulation of neuronal redox homeostasis (Cuervo & Dice, 2000; Cuervo et al., 2004).”
BackgroundKaushik, S., & Cuervo, A. M. (2008) · Methods in molecular biology · doi:10.1007/978-1-59745-157-4_15 · Cited by 93
Self-citationLRRK2: a common pathway for parkinsonism, pathogenesis and prevention?
Taylor, J. P., Mata, I. F., & Farrer, M. J. (2006) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2005.12.004 · Cited by 94
Autophagic pathways and metabolic stress
Kaushik, S., Singh, R., & Cuervo, A. M. (2010) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2010.01263.x · Cited by 95
Self-citationRemoving Protein Aggregates: The Role of Proteolysis in Neurodegeneration
Nijholt, D. A. T., Kimpe, L. D., Elfrink, H. L., Hoozemans, J. J. M., & Scheper, W. (2011) · Current Medicinal Chemistry · doi:10.2174/092986711795843236 · Cited by 96
Stem Cell-Based Therapies for Parkinson Disease
Liu, Z., & Cheung, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218060 · Cited by 98
Calabrese, G., Molzahn, C. M., & Mayor, T. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102062 · Cited by 92
“Indeed, CMA has been shown to also to regulate mutHTT clearance with the participation of Hsc70 (292).”
BackgroundInfluentialRout, A. K., Strub, M., Piszczek, G., & Tjandra, N. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.609446 · Cited by 102
Oh, S. Y., He, F., Krans, A., Frazer, M. A., Taylor, J. P., Paulson, H. L., & Todd, P. K. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv165 · Cited by 92
Endo-lysosomal proteins and ubiquitin CSF concentrations in Alzheimer’s and Parkinson’s disease
Sjödin, S., Brinkmalm, G., Öhrfelt, A., Parnetti, L., Paciotti, S., Hansson, O., Hardy, J., Blennow, K., Zetterberg, H., & Brinkmalm, A. (2019) · Alzheimer s Research & Therapy · doi:10.1186/s13195-019-0533-9 · Cited by 94
Drobny, A., Huarcaya, S. P., Dobert, J. P., Kluge, A., Bunk, J., Schlothauer, T., & Zunke, F. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2022.119243 · Cited by 94
Chapter 5 Autophagic Clearance of Aggregate‐Prone Proteins Associated with Neurodegeneration
Sarkar, S., Ravikumar, B., & Rubinsztein, D. C. (2009) · Methods in Enzymology · doi:10.1016/s0076-6879(08)04005-6 · Cited by 79
Genes associated with Parkinson syndrome
Biskup, S., Gerlach, M., Kupsch, A. R., Reichmann, H., Riederer, P. F., Vieregge, P., Wüllner, U., & Gasser, T. (2008) · Journal of Neurology · doi:10.1007/s00415-008-5005-2 · Cited by 91
“Mutant α-SYN also binds to receptors, but instead of being translocated sufficiently blocks not only its own uptake but also uptake of other substrates [12].”
BackgroundScheper, W., & Hoozemans, J. J. M. (2009) · Current Medicinal Chemistry · doi:10.2174/092986709787458506 · Cited by 92
von Coelln, R., Thomas, B., Andrabi, S. A., Lim, K. L., Savitt, J. M., Saffary, R., Stirling, W. L. H., Bruno, K. J., Hess, E. J., Lee, M. K., et al. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0414-06.2006 · Cited by 92
“…than being degraded in neurons of patients suffering from idiopathic PD. Evidence for proteasomal degradation, possibly independent of ubiquitination, as well as for autophagic degradation by lysosomes has been reported previously (Bennett et al., 1999; Tofaris et al., 2001; Cuervo et al., 2004).”
BackgroundThe Role of HSP70 and Its Co-chaperones in Protein Misfolding, Aggregation and Disease
Duncan, E. J., Cheetham, M. E., Chapple, J. P., & van der Spuy, J. (2014) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-3-319-11731-7_12 · Cited by 96
Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD
Esteves, A. R., Arduíno, D. M., Silva, D. F., Oliveira, C. R., & Cardoso, S. M. (2011) · Parkinson s Disease · doi:10.4061/2011/693761 · Cited by 90
“Being a soluble protein, alpha-syn can be degraded by CMA because it contains the CMA recognition targeting motif [253].”
Rockenstein, E. M., Schwach, G., Ingolić, E., Adame, A., Crews, L. A., Mante, M., Pfragner, R., Schreiner, E., Windisch, M., & Masliah, E. (2005) · Journal of Neuroscience Research · doi:10.1002/jnr.20446 · Cited by 90
“Furthermore, recent studies have shown that degradation of mutant a-synuclein by chaperone-mediated autophagy is impaired (Cuervo et al., 2004).”
BackgroundThe Role of Autophagy in Age-Related Neurodegeneration
McCray, B. A., & Taylor, J. P. (2007) · Neurosignals · doi:10.1159/000109761 · Cited by 90
“Chaperone-mediated autophagy has also been found to contribute to the degradation of α-synuclein, a process that is impaired by disease-causing mutations [”
Backgroundβ-synuclein modulates α-synuclein neurotoxicity by reducing α-synuclein protein expression
Fan, Y., Limprasert, P., Murray, I. V. J., Smith, A. C., Lee, V. M. ‐., Trojanowski, J. Q., Sopher, B. L., & Spada, A. R. L. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl242 · Cited by 90
Synphilin-1 attenuates neuronal degeneration in the A53T -synuclein transgenic mouse model
Smith, W. W., Liu, Z. W., Liang, Y., Masuda, N., Swing, D. A., Jenkins, N. A., Copeland, N. G., Troncoso, J. C., Pletnikov, M. V., Dawson, T. M., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq086 · Cited by 94
Autophagy and neurodegenerative disorders.
Kesidou, E., Lagoudaki, R., Touloumi, O., Poulatsidou, K.-N., & Simeonidou, C. (2013) · PubMed · doi:10.3969/j.issn.1673-5374.2013.24.007 · Cited by 91
“Moreover, missense mutations of α-synuclein or dopamine mediated modifications result in even greater impairment of CMA [52] .”
van Veen, S., Sørensen, D. M., Holemans, T., Holen, H. W., Palmgren, M. B., & Vangheluwe, P. (2014) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2014.00048 · Cited by 90
“…can have a significant impact on the basal fusogenic properties of synaptic vesicles. α -synuclein aggregates accumulate in PD and are cleared via various routes, mainly including the ubiquitin-proteasome sys-tem, autophagy and lysosomal degradation pathways (Webb et al., 2003; Cuervo et al., 2004).”
BackgroundLysosome and calcium dysregulation in Alzheimer's disease: partners in crime
McBrayer, M. K., & Nixon, R. A. (2013) · Biochemical Society Transactions · doi:10.1042/bst20130201 · Cited by 92
Perera, N. D., Sheean, R. K., Lau, C. L., Shin, Y. S., Beart, P. M., Horne, M. K., & Turner, B. J. (2017) · Autophagy · doi:10.1080/15548627.2017.1385674 · Cited by 89
Selective vulnerability in α-synucleinopathies
Alegre‐Abarrategui, J., Brimblecombe, K. R., Roberts, R. F., Velentza‐Almpani, E., Tilley, B. S., Bengoa‐Vergniory, N., & Proukakis, C. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02010-2 · Cited by 90
Wu, Y., Chen, C., Chao, C.-Y., Ro, L.-S., Lyu, R.-K., Chang, K., & Lee-Chen, G.-J. (2007) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2006.105940 · Cited by 90
“Further evidence suggests that processing of α-synuclein occurs in lysosomes,”
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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