Wild Type α-Synuclein Is Degraded by Chaperone-mediated Autophagy and Macroautophagy in Neuronal Cells*

By Tereza Vogiatzi, M. Xilouri, K. Vekrellis, Leonidas Stefanis. Journal of Biological Chemistry, 2008

669 citations recorded by the source corpus.

α-Synuclein (ASYN) is crucial in Parkinson disease (PD) pathogenesis. Increased levels of wild type (WT) ASYN expression are sufficient to cause PD in humans. The manner of post-transcriptional regulation of ASYN levels is controversial. Previously, we had shown that WT ASYN can be degraded by chaperone-mediated autophagy (CMA) in isolated liver lysosomes. Whether this occurs in a cellular and, in particular, in a neuronal cell context is unclear. Using a mutant ASYN form that lacks the CMA recognition motif and RNA interference against the rate-limiting step in the CMA pathway, Lamp2a, we show here that CMA is indeed involved in WT ASYN degradation in PC12 and SH-SY5Y cells, and in primary cortical and midbrain neurons. However, the extent of involvement varies between cell types, potentially because of differences in compensatory mechanisms. CMA inhibition leads to an accumulation of soluble high molecular weight and detergent-insoluble species of ASYN, suggesting that CMA dysfunction may play a role in the generation of such aberrant species in PD. ASYN and Lamp2a are developmentally regulated in parallel in cortical neuron cultures and in vivo in the central nervous system, and they physically interact as indicated by co-immunoprecipitation. In contrast to previous reports, inhibition of macroautophagy, but not the proteasome, also leads to WT ASYN accumulation, suggesting that this lysosomal pathway is also involved in normal ASYN turnover. These results indicate that CMA and macroautophagy are important pathways for WT ASYN degradation in neurons and underline the importance of CMA as degradation machinery in the nervous system.

Subfields: Cellular and Molecular Neuroscience, Epidemiology, Neurology

View Paper: https://www.semanticscholar.org/paper/defee60133ef28a3eae9e0fe29d4a2edbe4a66ae

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Citations in the corpus

Prion-like transmission of protein aggregates in neurodegenerative diseases (2010, background): “Cells can release aggregates either by a vesicle-mediated exocytic process, perhaps resulting from incomplete autophagocytosi”
Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, positive): “…Parkinson's disease Macroautophagy degrades wild-type and mutated a-syn (Vogiatzi et al., 2008) CMA degrades wild-type a-syn (Cuervo et al., 2004; Vogiatzi et al., 2008) CMA is inhibited by mutated a-syn (Cuervo et al., 2004) CMA activity is reduced in the brain of PD patient (Alvarez-Erviti et…”
Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. (2009, background): “The autophagy-lysosome pathway, including chaperone-mediated autophagy and macroautophagy is an important mechanism for the degradation of cellular -synuclein (Vogiatzi et al., 2008).”
Cell-Produced α-Synuclein Is Secreted in a Calcium-Dependent Manner by Exosomes and Impacts Neuronal Survival (2010, methodology): “Cultures of rat (embryonic day 18) cortical neurons were prepared as described previously (Vogiatzi et al., 2008).”
α-Synuclein in Parkinson's disease. (2012, background): “…the bulk of degradation of at least monomeric WT a-synuclein in neuronal cell systems occurs through the lysosomal pathways of chaperone-mediated autophagy (CMA) and macroautophagy (Paxinou et al. 2001; Webb et al. 2003; Cuervo et al. 2004; Lee et al. 2004; Vogiatzi et al. 2008; Mak et al. 2010).”
Exosomal cell-to-cell transmission of alpha synuclein oligomers (2012, background): “It is now thought that αsyn can be degraded by either the proteasome or by autophagy and both macroautophagy and CMA have been reported to contribute to αsyn degradation [101-104].”
Pathogenic Lysosomal Depletion in Parkinson's Disease (2010, background): “Relevant to PD, macroautophagy is the primary mechanism by which longlived proteins, such -synuclein, are degraded and is the only mechanism by which entire organelles, such as mitochondria, are recycled (C. T. Chu et al., 2007; Mizushima, 2007; Vogiatzi et al., 2008).”