Abstract
Dopaminergic (DA) cell death in Parkinson's disease (PD) is associated with the gradual appearance of neuronal protein aggregates termed Lewy bodies (LBs) that are comprised of vesicular membrane structures and dysmorphic organelles in conjunction with the protein alpha-Synuclein (alpha-Syn). Although the exact mechanism of neuronal aggregate formation and death remains elusive, recent research suggests alpha-Syn-mediated alterations in the lysosomal degradation of aggregated proteins and organelles - a process termed autophagy. Here, we used a combination of molecular biology and immunochemistry to investigate the effect of alpha-Syn on autophagy turnover in cultured human DA neurons and in human post-mortem brain tissue. We found alpha-Syn overexpression to reduce autophagy turnover by compromising the fusion of autophagosomes with lysosomes, thus leading to a decrease in the formation of autolysosomes. In accord with a compensatory increase in the plasma membrane fusion of autophagosomes, alpha-Syn enhanced the number of extracellular vesicles (EV) and the abundance of autophagy-associated proteins in these EVs. Mechanistically, alpha-Syn decreased the abundance of the v-SNARE protein SNAP29, a member of the SNARE complex mediating autophagolysosome fusion. In line, SNAP29 knockdown mimicked the effect of alpha-Syn on autophagy whereas SNAP29 co-expression reversed the alpha-Syn-induced changes on autophagy turnover and EV release and ameliorated DA neuronal cell death. In accord with our results from cultured neurons, we found a stage-dependent reduction of SNAP29 in SNc DA neurons from human post-mortem brain tissue of Lewy body pathology (LBP) cases. In summary, our results thus demonstrate a previously unknown effect of alpha-Syn on intracellular autophagy-associated SNARE proteins and, as a consequence, a reduced autolysosome fusion. As such, our findings will therefore support the investigation of autophagy-associated pathological changes in PD
Item Type: | Journal article |
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Faculties: | Medicine Medicine > Munich Cluster for Systems Neurology (SyNergy) |
Subjects: | 600 Technology > 610 Medicine and health |
URN: | urn:nbn:de:bvb:19-epub-102505-7 |
ISSN: | 2041-4889 |
Language: | English |
Item ID: | 102505 |
Date Deposited: | 05. Jun 2023, 15:40 |
Last Modified: | 07. Jun 2024, 13:49 |
DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198 |