1. Alpha-Synuclein defects autophagy by impairing SNAP29-mediated autophagosome-lysosome fusion
- Author
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Thomas Arzberger, Pan Gao, Günter U. Höglinger, Matthias Höllerhage, Thomas Koeglsperger, Qilin Tang, and Jochen Herms
- Subjects
Models, Molecular ,Cancer Research ,Autolysosome ,Parkinson's disease ,Cell death in the nervous system ,metabolism [Qc-SNARE Proteins] ,Membrane Fusion ,metabolism [Lysosomes] ,chemistry.chemical_compound ,metabolism [Extracellular Vesicles] ,Plasma membrane fusion ,Sequestosome-1 Protein ,metabolism [alpha-Synuclein] ,Gene knockdown ,metabolism [Qb-SNARE Proteins] ,Chemistry ,metabolism [Dopaminergic Neurons] ,Middle Aged ,Qb-SNARE Proteins ,metabolism [Autophagosomes] ,Cell biology ,ddc ,Substantia Nigra ,Gene Knockdown Techniques ,alpha-Synuclein ,Article ,Microtubule-Associated Proteins ,Intracellular ,Protein Binding ,Programmed cell death ,Immunology ,Models, Biological ,Biophysical Phenomena ,Cell Line ,Cellular and Molecular Neuroscience ,Extracellular Vesicles ,ddc:570 ,metabolism [Sequestosome-1 Protein] ,Organelle ,metabolism [Substantia Nigra] ,Autophagy ,Humans ,Qc-SNARE Proteins ,pathology [Substantia Nigra] ,Aged ,Alpha-synuclein ,Melanins ,pathology [Lewy Bodies] ,QH573-671 ,Dopaminergic Neurons ,Autophagosomes ,metabolism [Microtubule-Associated Proteins] ,Cell Biology ,metabolism [Melanins] ,nervous system ,Lewy Bodies ,Cytology ,Energy Metabolism ,Lysosomes - 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
- Published
- 2021