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

Cell Death Dis. 2018 Jul 9;9(7):757. doi: 10.1038/s41419-018-0816-2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagosomes / metabolism
  • Autophagy / physiology*
  • Blotting, Western
  • Cell Line
  • Exosomes / metabolism*
  • Humans
  • RNA, Small Interfering / metabolism
  • Real-Time Polymerase Chain Reaction
  • alpha-Synuclein / metabolism*


  • RNA, Small Interfering
  • alpha-Synuclein