期刊
CELL DEATH & DISEASE
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-018-0816-2
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资金
- ParkinsonFonds Germany (Hypothesis-Free Compound Screen in a New Human Neuronal Model of Wild Type AlphaSynuclein Induced Death)
- Deutsche Forschungsgemeinschaft (DFG) [HO2402/6-2]
- German Federal Ministry of Education and Research (BMBF) [01KU1403A, 01EK1605A, 031A430E]
- Bavarian Ministry for Education, Culture, Science and Art [8810001412]
- NOMIS foundation (FTLD project)
- Joint Project HIT-Tau (High Throughput Approaches for the Individualized Therapy of Tau-Related Diseases-TP2) [01EK1605C]
Accumulation of pathological alpha-synuclein aggregates plays a major role in Parkinson's disease. Macroautophagy is a mechanism to degrade intracellular protein aggregates by wrapping them into autophagosomes, followed by fusion with lysosomes. We had previously shown that pharmacological activation of macroautophagy protects against alpha-synuclein-induced toxicity in human neurons. Here, we hypothesized that inhibition of macroautophagy would aggravate alpha-synuclein-induced cell death. Unexpectedly, inhibition of autophagosome formation by silencing of ATG5 protected from alpha-synuclein-induced toxicity. Therefore, we studied alternative cellular mechanisms to compensate for the loss of macroautophagy. ATG5 silencing did not affect the ubiquitin-proteasome system, chaperone systems, chaperone-mediated autophagy, or the unfolded protein response. However, ATG5 silencing increased the secretion of alpha-synuclein via exosomes. Blocking exosomal secretion exacerbated alpha-synuclein-induced cell death. We conclude that exosomal secretion of alpha-synuclein is increased after impaired formation of autophagosomes to reduce the intracellular alpha-synuclein burden. This compensatory mechanism prevents alpha-synuclein-induced neuronal cell death.
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