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shRNA-Based Screen Identifies Endocytic Recycling Pathway Components That Act as Genetic Modifiers of Alpha-Synuclein Aggregation, Secretion and Toxicity

2016-04-28Journal article Open access
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dc.contributor.authorGonçalves, Susana A
dc.contributor.authorMacedo, Diana
dc.contributor.authorRaquel, Helena
dc.contributor.authorSimões, Pedro D
dc.contributor.authorGiorgini, Flaviano
dc.contributor.authorRamalho, José S
dc.contributor.authorBarral, Duarte C
dc.contributor.authorFerreira Moita, Luís
dc.contributor.authorOuteiro, Tiago Fleming
dc.date.accessioned2016-05-03T17:17:36Z
dc.date.available2016-05-03T17:17:36Z
dc.date.issued2016-04-28
dc.description.abstractAlpha-Synuclein (aSyn) misfolding and aggregation is common in several neurodegenerative diseases, including Parkinson's disease and dementia with Lewy bodies, which are known as synucleinopathies. Accumulating evidence suggests that secretion and cell-to-cell trafficking of pathological forms of aSyn may explain the typical patterns of disease progression. However, the molecular mechanisms controlling aSyn aggregation and spreading of pathology are still elusive. In order to obtain unbiased information about the molecular regulators of aSyn oligomerization, we performed a microscopy-based large-scale RNAi screen in living cells. Interestingly, we identified nine Rab GTPase and kinase genes that modulated aSyn aggregation, toxicity and levels. From those, Rab8b, Rab11a, Rab13 and Slp5 were able to promote the clearance of aSyn inclusions and rescue aSyn induced toxicity. Furthermore, we found that endocytic recycling and secretion of aSyn was enhanced upon Rab11a and Rab13 expression in cells accumulating aSyn inclusions. Overall, our study resulted in the identification of new molecular players involved in the aggregation, toxicity, and secretion of aSyn, opening novel avenues for our understanding of the molecular basis of synucleinopathies.pt_PT
dc.description.sponsorshipAxa Research Fund; FCT fellowships: (SFRH/BD/79337/2011, SFRH/BD/73429/2010); Marie Curie International Reintegration Grant: (PIRG05-GA-2009-247726); Fundação Luso-Americana para o Desenvolvimento (FLAD); European Research Council: (ERC-2014-CoG 647888- iPROTECTION); Parkinson’s UK; Michael J. Fox Foundation; DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain.pt_PT
dc.identifier.citationGonçalves SA, Macedo D, Raquel H, Simões PD, Giorgini F, Ramalho JS, et al. (2016) shRNA-Based Screen Identifies Endocytic Recycling Pathway Components That Act as Genetic Modifiers of Alpha-Synuclein Aggregation, Secretion and Toxicity. PLoS Genet 12(4): e1005995. doi:10.1371/ journal.pgen.1005995pt_PT
dc.identifier.doi10.1371/journal.pgen.1005995pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.7/591
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherPLOSpt_PT
dc.relation.publisherversionhttp://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005995pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectSecretionpt_PT
dc.subjectHyperexpression techniquespt_PT
dc.subjectOligomerspt_PT
dc.subjectToxicitypt_PT
dc.subjectCytotoxicitypt_PT
dc.subjectImmunoblottingpt_PT
dc.subjectImmunocytochemistrypt_PT
dc.subjectFluorescence microscopypt_PT
dc.titleshRNA-Based Screen Identifies Endocytic Recycling Pathway Components That Act as Genetic Modifiers of Alpha-Synuclein Aggregation, Secretion and Toxicitypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-OSM%2F104668%2F2008/PT
oaire.citation.endPage26pt_PT
oaire.citation.issue4pt_PT
oaire.citation.startPage1pt_PT
oaire.citation.titlePLOS Geneticspt_PT
oaire.citation.volume12pt_PT
oaire.fundingStream3599-PPCDT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication9042333c-6789-49e2-ad24-42fe30b2a8fb
relation.isProjectOfPublication.latestForDiscovery9042333c-6789-49e2-ad24-42fe30b2a8fb

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