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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“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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The effects of oxidative stress on parkin and other E3 ligases
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“In addition, chaperone-mediated autophagy has been shown to process wild-type a-synuclein (Cuervo et al. 2004).”
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“Notably, in contrast with the previous studies (Cuervo et al., 2004; Xilouri et al., 2009), we didn’t observe any changes in Hsc70 in α-Syn-treated striatum, possibly due to the specific brain regions and temporal point we examined.”
Monaco, A., & Fraldi, A. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00037 · Cited by 91
“…have shown that the aggregated forms of α-synuclein can bind the lysosome, thus impairing the chaperone-mediated autophagy, a selective autophagy pathway for degradation of cytosolic proteins (Cuervo et al., 2004; Martinez-Vicente et al., 2008) or inducing lysosomal rupture (Freeman et al., 2013).”
BackgroundRecombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models
Huarcaya, S. P., Drobny, A., Marques, A. R. A., Spiezio, A. D., Dobert, J. P., Balta, D., Werner, C. D., Rizo, T., Gallwitz, L., Bub, S., et al. (2022) · Autophagy · doi:10.1080/15548627.2022.2045534 · Cited by 93
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“tophagy and inhibited this pathway [29].”
Posttranslational Modification and Quality Control
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“Rat and mouse α-synuclein, containing the A53T substitution seen in familial forms of PD [122], are degraded by CMA [117,118,123], although this seems incongruent with findings for human A53T mutant α-synuclein [117].”
Genetic mutations and functions of PINK1
Kawajiri, S., Saiki, S., Sato, S., & Hattori, N. (2011) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2011.06.001 · Cited by 87
Autophagy as a Cellular Stress Response Mechanism in the Nervous System
Peker, N., & Gözüaçık, D. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2020.01.017 · Cited by 87
LRRK2 and α-Synuclein: Distinct or Synergistic Players in Parkinson’s Disease?
O’Hara, D. M., Pawar, G. N., Kalia, S. K., & Kalia, L. V. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00577 · Cited by 89
“…activity of LRRK2, as discussed below (Figure 3). α-Synuclein α-Synuclein contains a CMA recognition motif and is partially degraded in a CMA-dependent manner in isolated liver lysosomes, cell lines, neurons, and in vivo (Webb et al., 2003; Cuervo et al., 2004; Lee et al., 2004; Mak et al., 2010).”
BackgroundInfluentialPang, S. Y.-Y., Lo, R., Ho, P. W., Liu, H., Chang, E. E. S., Leung, C.-T., Malki, Y., Choi, Z. Y.-K., Wong, W. Y., Kung, M. H.-W., et al. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00281-6 · Cited by 86
Pathogenesis of α-Synuclein in Parkinson’s Disease: From a Neuron-Glia Crosstalk Perspective
Yi, S., Wang, L., Wang, H., Ho, M. S.-C., & Zhang, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232314753 · Cited by 96
ɑ‐Synuclein strains and the variable pathologies of synucleinopathies
Peelaerts, W., & Baekelandt, V. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13595 · Cited by 96
“1), 256--274 recognized by the constitutively expressed heat-shock cognate 70 protein that upon binding translocates to the lysosome (Auluck et al. 2002; Cuervo et al. 2004).”
BackgroundParkinson's disease and age: The obvious but largely unexplored link
Abdullah, R., Basak, I., Patil, K. S., Alves, G. W., Larsen, J. P., & Møller, S. G. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.09.014 · Cited by 87
“Furthermore, the pathogenic SNCA mutations A53T and A30P have the ability to block the uptake of damaged proteins by lysosomes causing inhibition of autophagy (Cuervo et al., 2004).”
BackgroundSpencer, B. J., Emadi, S., Desplats, P., Eleuteri, S., Michael, S. A., Kosberg, K. A., Shen, J., Rockenstein, E. M., Patrick, C., Adame, A., et al. (2014) · Molecular Therapy · doi:10.1038/mt.2014.129 · Cited by 85
RetractedPhytochemicals Bridging Autophagy Induction and Alpha-Synuclein Degradation in Parkinsonism
Limanaqi, F., Biagioni, F., Busceti, C. L., Ryskalin, L., Polzella, M., Frati, A., & Fornai, F. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20133274 · Cited by 87
Ono, K., Ikemoto, M., Kawarabayashi, T., Ikeda, M., Nishinakagawa, T., Hosokawa, M., Shoji, M., Takahashi, M., & Nakashima, M. (2009) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2009.03.002 · Cited by 85
“Aberrant a-Syn disturbed protein is turned over in the ER through the ubiquitin–proteasome pathway and chaperone-mediated autophagy pathway [29].”
BackgroundMitochondrial dynamics, cell death and the pathogenesis of Parkinson’s disease
Büeler, H. (2010) · APOPTOSIS · doi:10.1007/s10495-010-0465-0 · Cited by 87
Ryo, A., Togo, T., Nakai, T., Hirai, A., Nishi, M., Yamaguchi, A., Suzuki, K., Hirayasu, Y., Kobayashi, H., Perrem, K., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507026200 · Cited by 85
Bogaerts, V., Theuns, J., & Broeckhoven, C. V. (2007) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2007.00342.x · Cited by 91
“Pathogenic p.Ala30Pro and p.Ala53Thr SNCA was also shown to be poorly degraded by chaperone-mediated autophagy (CMA) (Cuervo et al. 2004).”
BackgroundAutophagy in Synucleinopathy: The Overwhelmed and Defective Machinery
Arotçarena, M.-L., Teil, M., & Dehay, B. (2019) · Cells · doi:10.3390/cells8060565 · Cited by 91
Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies
Arotcarena, M.-L., Bourdenx, M., Dutheil, N., Thiolat, M.-L., Doudnikoff, E., Dovero, S., Ballabio, A., Fernagut, P.-O., Meissner, W. G., Bezard, E., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.129719 · Cited by 84
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Enhanced Autophagy from Chronic Toxicity of Iron and Mutant A53T α-Synuclein
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Pathogenesis of Parkinson's disease: emerging role of molecular chaperones
Bandopadhyay, R., & de Belleroche, J. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.11.004 · Cited by 83
Molecular Insights into Parkinson's Disease
Rochet, J., Hay, B. A., & Guo, M. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385883-2.00011-4 · Cited by 87
Mitophagy in Parkinson’s Disease: Pathogenic and Therapeutic Implications
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Parkinson's disease in women: Mechanisms underlying sex differences
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A Critical Review of Zebrafish Models of Parkinson’s Disease
Doyle, J. M., & Croll, R. P. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.835827 · Cited by 94
“Impairments in lysosomal pathways, whether genetically induced or not, cause a reduction in α-synuclein degradation (Cuervo et al., 2004; Vogiatzi et al., 2008; Vázquez-Vélez and Zoghbi, 2021).”
BackgroundFu, R., Harn, H., Liu, S., Chen, C., Chang, W.-L., Chen, Y.-M., Huang, J.-E., Li, R.-J., Tsai, S.-Y., Hung, H., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0085305 · Cited by 89
“These influences may be compounded by PD-related dysregulation of chaperones [5], a continually accelerating loss in general cellular homeostasis [6,7].”
BackgroundShen, S., Zhang, P., Lovchik, M. A., Li, Y., Tang, L.-Y., Chen, Z., Zeng, R., Ma, D., Yuan, J., & Yu, Q. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200810183 · Cited by 84
“635HSP90 CLIENTS’ DEGRADATION THROUGH CMA • Shen et al. translocation into the lysosomal lumen (Cuervo et al., 2004).”
BackgroundArduíno, D. M., Esteves, A. R., Cortes, L., Silva, D. F., Patel, B., Grazina, M. M., Swerdlow, R. H., Oliveira, C. R., & Cardoso, S. M. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds309 · Cited by 87
Preserving Lysosomal Function in the Aging Brain: Insights from Neurodegeneration
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Lee, J., Rao, M. V., Yang, D., Stavrides, P. H., Im, E., Pensalfini, A., Huo, C., Sarkar, P., Yoshimori, T., & Nixon, R. A. (2018) · Autophagy · doi:10.1080/15548627.2018.1528812 · Cited by 82
“ALP abnormalities have been implicated inmajor neurodegenerative diseases, including AD [43,44], PD [45,46], and frontotemporal dementia [47].”
BackgroundAllnutt, A., Waters, A. K., Kesari, S., & Yenugonda, V. M. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00096 · Cited by 86
The Role of Chaperone-Mediated Autophagy in Cell Cycle Control and Its Implications in Cancer
Andrade-Tomaz, M., de Souza, I., Rocha, C. R. R., & Gomes, L. R. (2020) · Cells · doi:10.3390/cells9092140 · Cited by 84
Protein S-nitrosylation and oxidation contribute to protein misfolding in neurodegeneration
Nakamura, T., Oh, C.-K., Zhang, X., & Lipton, S. A. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.07.002 · Cited by 84
Role of Ubiquitin–Proteasome and Autophagy-Lysosome Pathways in α-Synuclein Aggregate Clearance
Sahoo, S., Padhy, A. A., Kumari, V., & Mishra, P. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02897-1 · Cited by 82
Lysosomes and α-synuclein form a dangerous duet leading to neuronal cell death
Bourdenx, M., Bézard, E., & Dehay, B. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2014.00083 · Cited by 88
“Interestingly, both CMA and proteasome can degrade the two proteins associated with autosomal dominant inheritance of PD, i.e., α-syn (PARK1/PARK4 locus) and Leucine-rich repeat kinase 2 (LRRK2–PARK8 locus) (Webb et al., 2003; Cuervo et al., 2004; Orenstein et al., 2013).”
BackgroundInfluentialProgress in the pathogenesis and genetics of Parkinson's disease
Mizuno, Y., Hattori, N., Kubo, S., Sato, S., Nishioka, K., Hatano, T., Tomiyama, H., Funayama, M., Machida, Y., & Mochizuki, H. (2008) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2008.2273 · Cited by 86
“…for degradation by the chaperone-mediated autophagy pathway; however, mutant A53T and A30P proteins can bind to the chaperon-mediated autophagy-pathway receptor on the lysosomal membrane, but act as uptake blockers inhibiting their own degradation and that of other proteins (Cuervo et al. 2004).”
BackgroundNutrient‐driven O‐Glc NA c in proteostasis and neurodegeneration
Akan, I., Stichelen, S. O.-V., Bond, M. R., & Hanover, J. A. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14242 · Cited by 84
“Mutation of asynuclein in PD yields aggregates than cannot be degraded by chaperone-mediated autophagy (Cuervo et al. 2004).”
BackgroundInflammatory and Cell Death Pathways in Brain and Peripheral Blood in Parkinson’s Disease
Macchi, B., Paola, R. D., Marino‐Merlo, F., Felice, M. R., Cuzzocrea, S., & Mastino, A. (2015) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527314666150225124928 · Cited by 80
Follett, J., Bugarcic, A., Yang, Z., Ariotti, N., Norwood, S. J., Collins, B. M., Parton, R. G., & Teasdale, R. D. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.703157 · Cited by 81
Pathogenesis of age-related HIV neurodegeneration
Mackiewicz, M., Overk, C., Achim, C. L., & Masliah, E. (2019) · Journal of NeuroVirology · doi:10.1007/s13365-019-00728-z · Cited by 89
“The protein clearance pathway includes mechanisms such as direct degradation of proteins by proteases, the proteasome, or via lysosomal pathways such as autophagy (Cuervo 2004).”
Backgroundα-synuclein impairs autophagosome maturation through abnormal actin stabilization
Sarkar, S., Olsen, A. L., Sygnecka, K., Lohr, K. M., & Feany, M. Β. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009359 · Cited by 82
Xu, Y., Deng, Y., & Qing, H. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13234 · Cited by 87
“They are ubiquitin-proteasome system pathway (Webb et al. 2003; Ebrahimi-Fakhari et al. 2011) and autophagy pathway (Cuervo et al. 2004; Spencer et al. 2009; Ebrahimi-Fakhari et al. 2011; Poehler et al. 2014).”
BackgroundHarrington, A. J., Yacoubian, T. A., Slone, S. R., Caldwell, K. A., & Caldwell, G. A. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.2606-11.2012 · Cited by 82
“Lysosomal targeting of misfolded and aggregated proteins for degradation, including -syn, has been shown to be largely mediated by macroautophagy and chaperone-mediated autophagy (CMA) (Webb et al., 2003; Cuervo et al., 2004).”
BackgroundWang, J.-D., Cao, Y.-L., Li, Q., Yang, Y., Jin, M., Chen, D., Wang, F., Wang, G., Qin, Z., Hu, L., et al. (2015) · Autophagy · doi:10.1080/15548627.2015.1100930 · Cited by 82
Role of Chaperone-Mediated Autophagy Dysfunctions in the Pathogenesis of Parkinson’s Disease
Sala, G., Marinig, D., Arosio, A., & Ferrarese, C. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00157 · Cited by 82
“Mutant A30P and A53T asyn bind to lamp2A with a higher affinity without being internalized and degraded, thus preventing the binding of other substrates (Cuervo et al., 2004).”
BackgroundGenetics of SynucleinopathiesPreprint
Nussbaum, R. L. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024109 · Cited by 85
“It is very likely that these point mutations prolonga-synuclein half-life (Cuervo et al. 2004; Fishbein et al. 2014) by interfering with lysosomal degradation (Fraidi et al. 2016).”
BackgroundFan, D., Liu, L., Wu, Z., & Cao, M. (2018) · Current Neuropharmacology · doi:10.2174/1570159x16666180419141613 · Cited by 80
“It has been demonstrated that autophagy is a major clearance pathway for the removal of intracytosolic aggregate-prone proteins associated with AD (mutant tau) and PD (mutant a-synuclein) [157-165].”
BackgroundSelective neuronal vulnerability in Parkinson's disease
González‐Rodríguez, P., Zampese, E., & Surmeier, D. J. (2020) · Progress in brain research · doi:10.1016/bs.pbr.2020.02.005 · Cited by 80
Jayaraj, R. L., Beiram, R., Azimullah, S., Meeran, M. F. N., Ojha, S. K., Adem, A., & Jalal, F. Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207670 · Cited by 82
Hinault, M., Cuendet, A. F. H., Mattoo, R. U. H., Mensi, M., Dietler, G., Lashuel, H. A., & Goloubinoff, P. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.127753 · Cited by 79
Increased α-synuclein phosphorylation and nitration in the aging primate substantia nigra
McCormack, A. L., Mak, S. K., & Monte, D. A. D. (2012) · Cell Death and Disease · doi:10.1038/cddis.2012.50 · Cited by 80
“of aging as well as in some age-related diseases, including PD.(21,22) It is also noteworthy that phosphorylated and nitrated a-synuclein are less susceptible to CMA degradation than the unmodified protein,(23) a feature that could contribute to their intraneuronal accumulation.”
BackgroundEffect of Trehalose on PC12 Cells Overexpressing Wild-Type or A53T Mutant α-synuclein
Lan, D.-M., Liu, F., Zhao, J., Chen, Y., Wu, J.-J., Ding, Z., Yue, Z., Ren, H., Jiang, Y., & Wang, J. (2012) · Neurochemical Research · doi:10.1007/s11064-012-0823-0 · Cited by 83
“With respect to autophagy, three main types have been confirmed, including Chaperone Mediated Autophagy (CMA) [23], microautophagy and macroautophagy [24].”
BackgroundHigashi, S., Moore, D. J., Yamamoto, R., Minegishi, M., Sato, K., Togo, T., Katsuse, O., Uchikado, H., Furukawa, Y., Hino, H., et al. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181b44ed8 · Cited by 81
Molecular Events Underlying Parkinson’s Disease – An Interwoven Tapestry
Lim, K., & Zhang, C. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00033 · Cited by 82
“Membrane bound α-synuclein species harboring disease-associated mutations or those modified by DA bind to the CMA lysosomal receptor with high affinity but are poorly translocated, which allow them time to seed the formation of oligomeric complexes on the membrane surface that consequently places the translocation com…”
BackgroundRothaug, M., Stroobants, S., Schweizer, M., Peters, J., Zunke, F., Allerding, M., D’Hooge, R., Säftig, P., & Blanz, J. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0182-y · Cited by 82
“Finally, despite the fact that down-regulation of LAMP-2 was reported to lead to an accumulation of another CMA substrate, α-syn in cultured neuronal cells [19,47], complete loss of LAMP-2 expression in murine brain did not cause a significant accumulation of either monomeric or high-molecular weight species of α-syn…”
BackgroundDysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson's disease
Pitcairn, C., Wani, W. Y., & Mazzulli, J. R. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.03.008 · Cited by 75
Are dopamine derivatives implicated in the pathogenesis of Parkinson's disease?
Bisaglia, M., Filograna, R., Beltramini, M., & Bubacco, L. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2013.12.009 · Cited by 81
Post, M. R., Lieberman, O. J., & Mosharov, E. V. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00161 · Cited by 82
“CMA cytosolic substrates contain a KFERQ-like motif that can be recognized by the chaperone protein cytHsc70 that delivers them to a lysosomal associated membrane protein (LAMP2A).”
BackgroundInfluentialTóth, M. L., Šimon, P., Kovács, A., & Vellai, T. (2007) · Journal of Cell Science · doi:10.1242/jcs.03401 · Cited by 82
“Degradation of normal -synuclein has been shown to occur via chaperone-mediated autophagy (Cuervo et al., 2004).”
BackgroundMolecular pathogenesis of Parkinson's disease: update
Saiki, S., Sato, S., & Hattori, N. (2011) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2011-301205 · Cited by 85
The association between mutations in the lysosomal protein glucocerebrosidase and parkinsonism
DePaolo, J., Göker-Alpan, Ö., Samaddar, T., Lopez, G. J., & Sidransky, E. (2009) · Movement Disorders · doi:10.1002/mds.22538 · Cited by 79
Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts
Teil, M., Arotçarena, M.-L., Faggiani, E., Laferrière, F., Bézard, E., & Dehay, B. (2020) · Biomolecules · doi:10.3390/biom10030391 · Cited by 80
Reciprocal regulation of chaperone-mediated autophagy and the circadian clock
Juste, Y. R., Kaushik, S., Bourdenx, M., Aflakpui, R., Bandyopadhyay, S., García, F., Díaz, A., Lindenau, K. L., Tu, V., Krause, G. J., et al. (2021) · Nature Cell Biology · doi:10.1038/s41556-021-00800-z · Cited by 82
Self-citationA β-synuclein mutation linked to dementia produces neurodegeneration when expressed in mouse brain
Fujita, M., Sugama, S., Sekiyama, K., Sekigawa, A., Tsukui, T., Nakai, M., Waragai, M., Takenouchi, T., Takamatsu, Y., Wei, J., et al. (2010) · Nature Communications · doi:10.1038/ncomms1101 · Cited by 78
“Moreover, LC3-positive dots were observed in the globules with an increased amount of LC3-II, a marker of autophagosome”
BackgroundChaperone-mediated autophagy: Dice's 'wild' idea about lysosomal selectivity
Cuervo, A. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3150 · Cited by 94
Self-citationThe Neurobiology of LRRK2 and its Role in the Pathogenesis of Parkinson’s Disease
Rideout, H. J., & Stefanis, L. (2013) · Neurochemical Research · doi:10.1007/s11064-013-1073-5 · Cited by 82
Self-citationRelease and uptake of pathologic alpha-synuclein
Grozdanov, V., & Danzer, K. M. (2018) · Cell and Tissue Research · doi:10.1007/s00441-017-2775-9 · Cited by 75
Beilina, A., Bonet-Ponce, L., Kumaran, R., Kordich, J. J., Ishida, M., Mamais, A., Kaganovich, A., Saez-Atienzar, S., Gershlick, D. C., Roosen, D. A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107614 · Cited by 82
“Thus, as a-synuclein is predominantly degraded through lysosomal pathways (Cuervo et al., 2004; Gao et al., 2008), we speculate that chronic lysosomal dysfunction may be important in the formation of PD Lewy pathology.”
Targeting the Progression of Parkinsons Disease
George, J., Mok, S., Moses, D., Wilkins, S., Bush, A., Cherny, R., & Finkelstein, D. (2009) · Current Neuropharmacology · doi:10.2174/157015909787602814 · Cited by 77
“Wild type synuclein has a half life of 48 hours while the A53T mutation has an approximately 50% longer half life [245] suggesting that these mutant proteins are selectively preventing degradation via the lysosome-mediated pathway [78].”
BackgroundMethods to study chaperone-mediated autophagy
Patel, B., & Cuervo, A. M. (2015) · Methods · doi:10.1016/j.ymeth.2015.01.003 · Cited by 77
Self-citationAutophagy and neurodegeneration
Ventruti, A., & Cuervo, A. M. (2007) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-007-0068-5 · Cited by 82
“Degradation of wild type B -synuclein by the UPS and by CMA has been well reported [ 40 ,51,52], whereas the mutant and toxic forms of the protein are cleared by macroautophagy [20,52].”
BackgroundResultInfluentialSelf-citationChaperone-mediated autophagy prevents apoptosis by degrading BBC3/PUMA
Xie, W. D., Zhang, L., Jiao, H., Guan, L., Zha, J., Li, X., Wu, M., Wang, Z., Han, J., & You, H. (2015) · Autophagy · doi:10.1080/15548627.2015.1075688 · Cited by 82
Influence of Normal Aging on Brain Autophagy: A Complex Scenario
Loeffler, D. A. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00049 · Cited by 79
“…between these two autophagic mechanisms (Figure 3) (reviewed by Wu et al., 2015); if the activity of one is reduced, the activity of the other may increase in an effort to maintain protein homeostasis (Cuervo et al., 2004; Massey et al., 2006a,b, 2008; Kaushik et al., 2008; Wang et al., 2010).”
BackgroundProtein Quality Control in Neurodegenerative Disease
Gestwicki, J. E., & Garza, D. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385883-2.00003-5 · Cited by 80
Lu, J., Wang, C., Cheng, X., Wang, R., Yan, X., He, P., Chen, H., & Yu, Z. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02484-0 · Cited by 80
The link between the SNCA gene and parkinsonism
Xu, W., Tan, L., & Yu, J. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.10.042 · Cited by 84
“In addition to affecting its spatial conformation, the mutant types were also found to modify its physiological function such as assisting role in CMA (Cuervo et al., 2004).”
BackgroundCharcot–Marie–Tooth disease and intracellular traffic
Bucci, C., Bakke, O., & Progida, C. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.03.003 · Cited by 78
Αlpha-Synuclein as a Mediator in the Interplay between Aging and Parkinson’s Disease
Bobela, W., Aebischer, P., & Schneider, B. L. (2015) · Biomolecules · doi:10.3390/biom5042675 · Cited by 75
“This is particularly important since CMA, along with UPS, are considered major degradation pathways for monomeric -syn [60,127].”
BackgroundQuality control gone wrong: mitochondria, lysosomal storage disorders and neurodegeneration
Osellame, L. D., & Duchen, M. R. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12453 · Cited by 77
“Alterations in autophagic rate have been implicated in the aforementioned neurodegenerative disorders as well as many lysosomal storage disorders (LSDs; Cuervo et al., 2004; Boland et al., 2008; Settembre et al., 2008a; Osellame et al., 2013).”
BackgroundInfluentialMechanisms of alpha-synuclein toxicity: An update and outlook
Brás, I. C., Xylaki, M., & Outeiro, T. F. (2019) · Progress in brain research · doi:10.1016/bs.pbr.2019.10.005 · Cited by 78
Nanomaterial-mediated autophagy: coexisting hazard and health benefits in biomedicine
Feng, X., Zhang, Y., Zhang, C., Lai, X., Zhang, Y., Wu, J., Hu, C., & Shao, L. (2020) · Particle and Fibre Toxicology · doi:10.1186/s12989-020-00372-0 · Cited by 75
Rabe, M., Soragni, A., Reynolds, N. P., Verdes, D., Liverani, E., Riek, R., & Seeger, S. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn3001312 · Cited by 75
Bonifati, V. (2007) · Neurochemical Research · doi:10.1007/s11064-007-9324-y · Cited by 77
“Several lines of evidence, including biochemical analysis, genomic and proteomic profiling of brain tissue, cell and animal models, implicated mitochondrial defects, oxidative stress, protein misfolding, proteasomal and lysosomal abnormalities in the pathogenesis [4–12].”
BackgroundMutations in the glucocerebrosidase gene and Parkinson disease: Phenotype–genotype correlation
Aharon‐Peretz, J., Badarny, S., Rosenbaum, H., & Gershoni‐Baruch, R. (2005) · Neurology · doi:10.1212/01.wnl.0000176987.47875.28 · Cited by 76
α-Synuclein in Parkinson disease and other neurodegenerative disorders
Eller, M., & Williams, D. R. (2011) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2011.077 · Cited by 79
Prigione, A., Piazza, F., Brighina, L., Begni, B., Galbussera, A., DiFrancesco, J. C., Andreoni, S., Piolti, R., & Ferrarese, C. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.04.022 · Cited by 76
Wu, G., Wang, X., Feng, X., Zhang, A., Li, J., Gu, K., Huang, J. A., Pang, S., Dong, H., Gao, H., et al. (2011) · Brain Research · doi:10.1016/j.brainres.2011.04.013 · Cited by 78
“Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy.”
Influential
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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