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

Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Soranou Efesiou 4, Athens, Greece.
Journal of Biological Chemistry (Impact Factor: 4.6). 07/2008; 283(35):23542-56. DOI: 10.1074/jbc.M801992200
Source: PubMed

ABSTRACT Alpha-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.

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    • "It may arise from either the gain of a new toxic function by the mutated GBA protein, or by a decrease in its enzymatic efficiency, or by both. The second and third possibilities are supported by the fact that the lysosomal-autophagy pathway is considered to be the main pathway through which SNCA is degraded (Vogiatzi et al., 2008; Machiya et al., 2010). Although Gaucher disease is a recessive disorder and heterozygous carriers of the disease are asymptomatic , lysosomal function might not be optimal in Gaucher disease heterozygotes. "
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    • "Other studies have focused on trying to understand what changes can be triggered by alpha-synuclein aggregation in cell metabolism. Some groups have reported than promoting apoptosis, energy depriving the cells and impairing proteasome degradation, among other cell insults, increase the levels of aggregated alpha-synuclein, suggesting that maintaining cellular homeostasis is critical for alpha-synuclein (Bellucci et al., 2008; Gentile et al., 2008; Vogiatzi et al., 2008). More importantly, primary cultures have been an invaluable model to study the seeding of alpha-synuclein pathological forms and the prion-like transmission from cell to cell. "
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    • "Although usually degraded through the proteasome, alpha‐synuclein requires unfolding for degradation and aggregating forms of this protein may require clearance through other pathways. Alpha‐synuclein, however, is also a target for chaperone mediated autophagy, which through interactions with LAMP‐ 2A and HSC (heat shock 70kDa proteins) targets the alpha‐synuclein directly to the lysosome (Alvarez‐Erviti et al. 2010; Alvarez‐Erviti et al. 2013; Vogiatzi et al. 2008). "
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