A metastable subproteome underlies inclusion formation in muscle proteinopathies
Authors
Ciryam, Prajwal
Antalek, Matthew
Cid, Fernando
Tartaglia, Gian Gaetano
Dobson, Christopher M.
Guettsches, Anne-Katrin
Eggers, Britta
Vorgerd, Matthias
Marcus, Katrin
Kley, Rudolf A.
Morimoto, Richard I.
Vendruscolo, Michele
Weihl, Conrad C.
Publication Date
2019-12-03Journal Title
Acta Neuropathologica Communications
Publisher
BioMed Central
Volume
7
Issue
1
Language
en
Type
Article
This Version
VoR
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Ciryam, P., Antalek, M., Cid, F., Tartaglia, G. G., Dobson, C. M., Guettsches, A., Eggers, B., et al. (2019). A metastable subproteome underlies inclusion formation in muscle proteinopathies. Acta Neuropathologica Communications, 7 (1)https://doi.org/10.1186/s40478-019-0853-9
Abstract
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.
Keywords
Research
Sponsorship
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR068797, K24AR073317)
National Institute of Neurological Disorders and Stroke (R21NS101588, R25NS070697)
National Institute on Aging (R37AG026647, P01AG054407, R56AG059579, RF1AG057296)
Medizinische Fakultät, Ruhr-Universität Bochum (FoRUM F755-12)
Identifiers
s40478-019-0853-9, 853
External DOI: https://doi.org/10.1186/s40478-019-0853-9
This record's URL: https://www.repository.cam.ac.uk/handle/1810/313919
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/