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A metastable subproteome underlies inclusion formation in muscle proteinopathies

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dc.contributor.author Ciryam, Prajwal
dc.contributor.author Antalek, Matthew
dc.contributor.author Cid Samper, Fernando, 1991-
dc.contributor.author Tartaglia, Gian Gaetano
dc.contributor.author Dobson, Christopher M.
dc.contributor.author Guettsches, Katrin
dc.contributor.author Eggers, Britta
dc.contributor.author Vorgerd, Matthias
dc.contributor.author Marcus, Katrin
dc.contributor.author Kley, Rudolf A.
dc.contributor.author Morimoto, Richard I.
dc.contributor.author Vendruscolo, Michele
dc.contributor.author Weihl, Conrad C.
dc.date.accessioned 2020-03-17T07:28:57Z
dc.date.available 2020-03-17T07:28:57Z
dc.date.issued 2019
dc.identifier.citation Ciryam P, Antalek M, Cid F, Tartaglia GG, Dobson CM, Guettsches AK, Eggers B, Vorgerd M, Marcus K, Kley RA, Morimoto RI, Vendruscolo M, Weihl CC. A metastable subproteome underlies inclusion formation in muscle proteinopathies. Acta Neuropathol Commun. 2019; 7(1):197. DOI: 10.1186/s40478-019-0853-9
dc.identifier.issn 2051-5960
dc.identifier.uri http://hdl.handle.net/10230/43901
dc.description.abstract Protein aggregation is a pathological feature of neurodegenerative disorders. We previously demonstrated that protein inclusions in the brain are composed of supersaturated proteins, which are abundant and aggregation-prone, and form a metastable subproteome. It is not yet clear, however, whether this phenomenon is also associated with non-neuronal protein conformational disorders. To respond to this question, we analyzed proteomic datasets from biopsies of patients with genetic and acquired protein aggregate myopathy (PAM) by quantifying the changes in composition, concentration and aggregation propensity of proteins in the fibers containing inclusions and those surrounding them. We found that a metastable subproteome is present in skeletal muscle from healthy patients. The expression of this subproteome escalate as proteomic samples are taken more proximal to the pathologic inclusion, eventually exceeding its solubility limits and aggregating. While most supersaturated proteins decrease or maintain steady abundance across healthy fibers and inclusion-containing fibers, proteins within the metastable subproteome rise in abundance, suggesting that they escape regulation. Taken together, our results show in the context of a human conformational disorder that the supersaturation of a metastable subproteome underlies widespread aggregation and correlates with the histopathological state of the tissue.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher BioMed Central
dc.relation.ispartof Acta Neuropathol Commun. 2019; 7(1):197
dc.rights © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title A metastable subproteome underlies inclusion formation in muscle proteinopathies
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1186/s40478-019-0853-9
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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