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

Fussi, Natascha; Höllerhage, Matthias; Chakroun, Tasnim; Nykänen, Niko-Petteri; Roesler, Thomas W.; Köglsperger, Thomas; Wurst, Wolfgang; Behrends, Christian und Höglinger, Guenter U. (2018): Exosomal secretion of alpha-synuclein as protective mechanism after upstream blockage of macroautophagy. In: Cell Death & Disease, Bd. 9, 757

Abstract

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2041-4889
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198