Altered degradation of α-synuclein (α-syn) has been implicated in the pathogenesis of Parkinson disease (PD). We have shown that α-syn can be degraded via chaperone-mediated autophagy (CMA), a selective lysosomal mechanism for degradation of cytosolic proteins. Pathogenic mutants of α-syn block lysosomal translocation, impairing their own degradation along with that of other CMA substrates. While pathogenic α-syn mutations are rare, α-syn undergoes posttranslational modifications, which may underlie its accumulation in cytosolic aggregates in most forms of PD. Using mouse ventral medial neuron cultures, SH-SY5Y cells in culture, and isolated mouse lysosomes, we have found that most of these posttranslational modifications of α-syn impair degradation of this protein by CMA but do not affect degradation of other substrates. Dopamine-modified α-syn, however, is not only poorly degraded by CMA but also blocks degradation of other substrates by this pathway. As blockage of CMA increases cellular vulnerability to stressors, we propose that dopamine-induced autophagic inhibition could explain the selective degeneration of PD dopaminergic neurons.
Marta Martinez-Vicente, Zsolt Talloczy, Susmita Kaushik, Ashish C. Massey, Joseph Mazzulli, Eugene V. Mosharov, Roberto Hodara, Ross Fredenburg, Du-Chu Wu, Antonia Follenzi, William Dauer, Serge Przedborski, Harry Ischiropoulos, Peter T. Lansbury, David Sulzer, Ana Maria Cuervo
Title and authors | Publication | Year |
---|---|---|
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The Autophagy Lysosomal Pathway and Neurodegeneration
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Biomedical Implications of Autophagy in Macromolecule Storage Disorders
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Autophagic and endo-lysosomal dysfunction in neurodegenerative disease
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Molecular brain | 2019 |
Autophagy and LRRK2 in the Aging Brain
F Albanese, S Novello, M Morari |
Frontiers in neuroscience | 2019 |
Combating Neurodegenerative Diseases with the Plant Alkaloid Berberine: Molecular Mechanisms and Therapeutic Potential
D Fan, L Liu, Z Wu, M Cao |
Current neuropharmacology | 2019 |
Chaperone Mediated Autophagy in the Crosstalk of Neurodegenerative Diseases and Metabolic Disorders
IE Alfaro, A Albornoz, A Molina, J Moreno, K Cordero, A Criollo, M Budini |
Frontiers in Endocrinology | 2019 |
Tumor cells induce LAMP2a expression in tumor-associated macrophage for cancer progression
R Wang, Y Liu, L Liu, M Chen, X Wang, J Yang, Y Gong, BS Ding, Y Wei, X Wei |
EBioMedicine | 2019 |
The usual suspects, dopamine and alpha-synuclein, conspire to cause neurodegeneration: Dopamine and alpha-synuclein collaborate in disease
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Movement disorders : official journal of the Movement Disorder Society | 2019 |
Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease
A di Domenico, G Carola, C Calatayud, M Pons-Espinal, JP Muñoz, Y Richaud-Patin, I Fernandez-Carasa, M Gut, A Faella, J Parameswaran, J Soriano, I Ferrer, E Tolosa, A Zorzano, AM Cuervo, A Raya, A Consiglio |
Stem Cell Reports | 2019 |
Dysfunction of Cellular Proteostasis in Parkinson’s Disease
Š Lehtonen, TM Sonninen, S Wojciechowski, G Goldsteins, J Koistinaho |
Frontiers in neuroscience | 2019 |
Found in Translation: The Utility of C. elegans Alpha-Synuclein Models of Parkinson’s Disease
A Gaeta, K Caldwell, G Caldwell |
Brain Sciences | 2019 |
Mechanisms and roles of mitophagy in neurodegenerative diseases
Y Wang, N Liu, B Lu |
CNS Neuroscience & Therapeutics | 2019 |
Autophagy in Synucleinopathy: The Overwhelmed and Defective Machinery
ML Arotcarena, M Teil, B Dehay |
Cells | 2019 |
Phytochemicals Bridging Autophagy Induction and Alpha-Synuclein Degradation in Parkinsonism
F Limanaqi, F Biagioni, CL Busceti, L Ryskalin, M Polzella, A Frati, F Fornai |
International journal of molecular sciences | 2019 |
Dihydromyricetin and Salvianolic acid B inhibit alpha-synuclein aggregation and enhance chaperone-mediated autophagy
JZ Wu, M Ardah, C Haikal, A Svanbergsson, M Diepenbroek, NN Vaikath, W Li, ZY Wang, TF Outeiro, OM El-Agnaf, JY Li |
Translational Neurodegeneration | 2019 |
Role of the endolysosomal system in Parkinson’s disease
DJ Vidyadhara, JE Lee, SS Chandra |
Journal of Neurochemistry | 2019 |
The role of chaperone‐mediated autophagy in neurotoxicity induced by alpha‐synuclein after methamphetamine exposure
L Sun, Y Lian, J Ding, Y Meng, C Li, L Chen, P Qiu |
Brain and Behavior | 2019 |
Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?
YC Wong, K Luk, K Purtell, SB Nanni, AJ Stoessl, LE Trudeau, Z Yue, D Krainc, W Oertel, JA Obeso, LA VolpicelliDaley |
Movement disorders : official journal of the Movement Disorder Society | 2019 |
Emerging therapies in Parkinson disease — repurposed drugs and new approaches
A Elkouzi, V Vedam-Mai, RS Eisinger, MS Okun |
Nature Reviews Neurology | 2019 |
The Role of Sex and Sex Hormones in Neurodegenerative Diseases
Vegeto E, Villa A, Della Torre S, Crippa V, Rusmini P, Cristofani R, Galbiati M, Maggi A, Poletti A |
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