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dc.contributor.authorCiryam, Prajwal
dc.contributor.authorAntalek, Matthew
dc.contributor.authorCid, Fernando
dc.contributor.authorTartaglia, Gian Gaetano
dc.contributor.authorDobson, Christopher M.
dc.contributor.authorGuettsches, Anne-Katrin
dc.contributor.authorEggers, Britta
dc.contributor.authorVorgerd, Matthias
dc.contributor.authorMarcus, Katrin
dc.contributor.authorKley, Rudolf A.
dc.contributor.authorMorimoto, Richard I.
dc.contributor.authorVendruscolo, Michele
dc.contributor.authorWeihl, Conrad C.
dc.date.accessioned2020-12-02T16:13:56Z
dc.date.available2020-12-02T16:13:56Z
dc.date.issued2019-12-03
dc.date.submitted2019-10-13
dc.identifier.others40478-019-0853-9
dc.identifier.other853
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/313919
dc.description.abstractAbstract: 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.languageen
dc.publisherBioMed Central
dc.subjectResearch
dc.titleA metastable subproteome underlies inclusion formation in muscle proteinopathies
dc.typeArticle
dc.date.updated2020-12-02T16:13:55Z
prism.issueIdentifier1
prism.publicationNameActa Neuropathologica Communications
prism.volume7
dc.identifier.doi10.17863/CAM.61022
dcterms.dateAccepted2019-11-21
rioxxterms.versionofrecord10.1186/s40478-019-0853-9
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.identifier.eissn2051-5960
pubs.funder-project-idNational Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR068797, K24AR073317)
pubs.funder-project-idNational Institute of Neurological Disorders and Stroke (R21NS101588, R25NS070697)
pubs.funder-project-idNational Institute on Aging (R37AG026647, P01AG054407, R56AG059579, RF1AG057296)
pubs.funder-project-idMedizinische Fakultät, Ruhr-Universität Bochum (FoRUM F755-12)


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