Exosomal secretion of α-synuclein as protective mechanism after upstream blockage of macroautophagy

Natascha Fussi, Matthias Höllerhage, Tasnim Chakroun, Niko Petteri Nykänen, Thomas W. Rösler, Thomas Koeglsperger, Wolfgang Wurst, Christian Behrends, Günter U. Höglinger

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Accumulation of pathological α-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 α-synuclein-induced toxicity in human neurons. Here, we hypothesized that inhibition of macroautophagy would aggravate α-synuclein-induced cell death. Unexpectedly, inhibition of autophagosome formation by silencing of ATG5 protected from α-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 α-synuclein via exosomes. Blocking exosomal secretion exacerbated α-synuclein-induced cell death. We conclude that exosomal secretion of α-synuclein is increased after impaired formation of autophagosomes to reduce the intracellular α-synuclein burden. This compensatory mechanism prevents α-synuclein-induced neuronal cell death.

Original languageEnglish
Article number757
JournalCell Death and Disease
Volume9
Issue number7
DOIs
StatePublished - 1 Jul 2018

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