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Exosomal secretion of alpha-synuclein as protective mechanism after upstream blockage of macroautophagy.
Cell Death Dis. 9:757 (2018)
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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5.638
1.497
61
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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
Language
Publication Year
2018
HGF-reported in Year
2018
ISSN (print) / ISBN
2041-4889
e-ISSN
2041-4889
Journal
Cell Death & Disease
Quellenangaben
Volume: 9,
Issue: 7,
Article Number: 757
Publisher
Nature Publishing Group
Publishing Place
Macmillan Building, 4 Crinan St, London N1 9xw, England
Reviewing status
Peer reviewed
Institute(s)
Institute of Developmental Genetics (IDG)
POF-Topic(s)
30204 - Cell Programming and Repair
Research field(s)
Genetics and Epidemiology
PSP Element(s)
G-500500-001
WOS ID
WOS:000438367000005
Scopus ID
85049757334
Erfassungsdatum
2018-07-24