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Alpha-Synuclein defects autophagy by impairing SNAP29-mediated autophagosome-lysosome fusion

Tang, Qilin, Gao, Pan, Arzberger, Thomas, Höllerhage, Matthias, Herms, Jochen, Höglinger, Günter, Koeglsperger, Thomas·2021·Cell Death & Disease
DOI 10.1038/s41419-021-04138-0PMC PMC8448865
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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 (α-Syn). Although the exact mechanism of neuronal aggregate formation and death remains elusive, recent research suggests α-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 α-Syn on autophagy turnover in cultured human DA neurons and in human post-mortem brain tissue. We found α-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, α-Syn enhanced the number of extracellular vesicles (EV) and the abundance of autophagy-associated proteins in these EVs. Mechanistically, α-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 α-Syn on autophagy whereas SNAP29 co-expression reversed the α-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 α-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

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  • α-Synuclein oligomers induce cellular stress responses, including aberrant autophagy-lysosome pathways, dysregulation of lipid metabolism, and a reduction in membrane trafficking.

    “α-Synuclein oligomers are known to induce cellular stress responses, including aberrant autophagy-lysosome pathways [161,162], dysregulation of lipid metabolism [163,164], and a reduction in membrane trafficking [4].”

    From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [162]

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Metadata

Authors
Tang, Q., Gao, P., Arzberger, T., Höllerhage, M., Herms, J., Höglinger, G., & Koeglsperger, T.
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2021-09-17
Volume
12
Issue
10
ISSN
2041-4889
DOI
10.1038/s41419-021-04138-0
PMC
PMC8448865
Cited by
103
References
14
Language
en
Licence
Funders
  • Deutsche Forschungsgemeinschaft (EXC 2145/ID 390857198, EXC 2145 SyNergy—ID 390857198, HO2402/18-1 MSAomics)
  • Bundesministerium für Bildung und Forschung (01KU1403A EpiPD; 01EK1605A HitTau)
  • Hilde-Ulrichs-Stiftung für Parkinsonforschung
  • Friede Springer Stiftung

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