Spatiotemporal proteomic profiling of Huntington's disease inclusions reveals widespread loss of protein function

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• dc.contributor.author Hosp, Fabianca
• dc.contributor.author Gutiérrez Ángel, Saraca
• dc.contributor.author Schaefer, Martin H.ca
• dc.contributor.author Cox, Jürgenca
• dc.contributor.author Meissner, Felixca
• dc.contributor.author Hipp, Mark Steffenca
• dc.contributor.author Hartl, F. Ulrichca
• dc.contributor.author Klein, Rüdigerca
• dc.contributor.author Dudanova, Irinaca
• dc.contributor.author Mann, Matthiasca
• dc.date.accessioned 2018-05-24T07:54:25Z
• dc.date.available 2018-05-24T07:54:25Z
• dc.date.issued 2017
• dc.description.abstract Aggregation of polyglutamine-expanded huntingtin exon 1 (HttEx1) in Huntington's disease (HD) proceeds from soluble oligomers to late-stage inclusions. The nature of the aggregates and how they lead to neuronal dysfunction is not well understood. We employed mass spectrometry (MS)-based quantitative proteomics to dissect spatiotemporal mechanisms of neurodegeneration using the R6/2 mouse model of HD. Extensive remodeling of the soluble brain proteome correlated with insoluble aggregate formation during disease progression. In-depth and quantitative characterization of the aggregates uncovered an unprecedented complexity of several hundred proteins. Sequestration to aggregates depended on protein expression levels and sequence features such as low-complexity regions or coiled-coil domains. In a cell-based HD model, overexpression of a subset of the sequestered proteins in most cases rescued viability and reduced aggregate size. Our spatiotemporally resolved proteome resource of HD progression indicates that widespread loss of cellular protein function contributes to aggregate-mediated toxicity.
• dc.description.sponsorship The research leading to these results has received funding from the Munich Cluster for Systems Neurology “SyNergy,” the European Research Council Synergy grant “ToPAG—Toxic protein aggregation in neurodegeneration” (ERC-2012-SyG_318987-ToPAG), and the Max Planck Society for the Advancement of Science.
• dc.format.mimetype application/pdf
• dc.identifier.citation Hosp F, Gutiérrez-Ángel S, Schaefer MH, Cox J, Meissner F, Hipp MS et al. Spatiotemporal Proteomic Profiling of Huntington’s Disease Inclusions Reveals Widespread Loss of Protein Function. Cell Reports. 2017 Nov;21(8):2291-303. DOI: 10.1016/j.celrep.2017.10.097
• dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2017.10.097
• dc.identifier.issn 2211-1247
• dc.identifier.uri http://hdl.handle.net/10230/34716
• dc.language.iso eng
• dc.publisher Elsevierca
• dc.relation.ispartof Cell Reports. 2017 Nov;21(8):2291-303
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/318987
• dc.rights © 2017 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword Huntington's disease
• dc.subject.keyword Cerebrospinal fluid
• dc.subject.keyword Inclusion bodies
• dc.subject.keyword Neurodegeneration
• dc.subject.keyword Quantitative proteomics
• dc.title Spatiotemporal proteomic profiling of Huntington's disease inclusions reveals widespread loss of protein functionca
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion