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Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose

2019-01-24Artigo científico Acesso aberto
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dc.contributor.authorHoffmann, Anna Carin
dc.contributor.authorMinakaki, Georgia
dc.contributor.authorMenges, Stefanie
dc.contributor.authorSalvi, Rachele
dc.contributor.authorSavitskiy, Sergey
dc.contributor.authorKazman, Aida
dc.contributor.authorVicente Miranda, Hugo
dc.contributor.authorMielenz, Dirk
dc.contributor.authorKlucken, Jochen
dc.contributor.authorWinkler, Jürgen
dc.contributor.authorXiang, Wei
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutionCentro de Estudos de Doenças Crónicas (CEDOC)
dc.contributor.pblNature Publishing Group
dc.date.accessioned2019-02-05T23:43:38Z
dc.date.available2019-02-05T23:43:38Z
dc.date.issued2019-01-24
dc.description.abstractCell-to-cell propagation of aggregated alpha synuclein (aSyn) has been suggested to play an important role in the progression of alpha synucleinopathies. A critical step for the propagation process is the accumulation of extracellular aSyn within recipient cells. Here, we investigated the trafficking of distinct exogenous aSyn forms and addressed the mechanisms influencing their accumulation in recipient cells. The aggregated aSyn species (oligomers and fibrils) exhibited more pronounced accumulation within recipient cells than aSyn monomers. In particular, internalized extracellular aSyn in the aggregated forms was able to seed the aggregation of endogenous aSyn. Following uptake, aSyn was detected along endosome-to-lysosome and autophagosome-to-lysosome routes. Intriguingly, aggregated aSyn resulted in lysosomal activity impairment, accompanied by the accumulation of dilated lysosomes. Moreover, analysis of autophagy-related protein markers suggested decreased autophagosome clearance. In contrast, the endocytic pathway, proteasome activity, and mitochondrial homeostasis were not substantially affected in recipient cells. Our data suggests that extracellularly added aggregated aSyn primarily impairs lysosomal activity, consequently leading to aSyn accumulation within recipient cells. Importantly, the autophagy inducer trehalose prevented lysosomal alterations and attenuated aSyn accumulation within aSyn-exposed cells. Our study underscores the importance of lysosomes for the propagation of aSyn pathology, thereby proposing these organelles as interventional targets.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent8350829
dc.identifier.doi10.1038/s41598-018-35811-8
dc.identifier.issn2045-2322
dc.identifier.otherPURE: 11447930
dc.identifier.otherPURE UUID: 99573eb7-2e62-433a-9c6c-8c3c40c41e73
dc.identifier.otherScopus: 85060517881
dc.identifier.otherPubMed: 30679445
dc.identifier.otherWOS: 000456553400109
dc.identifier.urihttp://www.scopus.com/inward/record.url?scp=85060517881&partnerID=8YFLogxK
dc.identifier.urlhttps://www.scopus.com/pages/publications/85060517881
dc.language.isoeng
dc.peerreviewedyes
dc.subjectGeneral
dc.titleExtracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehaloseen
dc.typejournal article
degois.publication.issue1
degois.publication.titleScientific Reports
degois.publication.volume9
dspace.entity.typePublication
rcaap.rightsopenAccess

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