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Fussi, N.* ; Höllerhage, M.* ; Chakroun, T.* ; Nykänen, N.P.* ; Rösler, T.W.* ; Koeglsperger, T.* ; Wurst, W. ; Behrends, C.* ; Höglinger, G.U.*

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

Cell Death Dis. 9:757 (2018)
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Open Access Gold
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Chaperone-mediated Autophagy; Unfolded Protein Response; Genome-wide Association; Parkinsons-disease; Molecular Chaperones; Neuronal Cells; Wild-type; Neurodegenerative Diseases; Extracellular Vesicles; Induced Toxicity
ISSN (print) / ISBN 2041-4889
e-ISSN 2041-4889
Quellenangaben Volume: 9, Issue: 7, Pages: , Article Number: 757 Supplement: ,
Publisher Nature Publishing Group
Publishing Place Macmillan Building, 4 Crinan St, London N1 9xw, England
Reviewing status Peer reviewed