A metastable subproteome underlies inclusion formation in muscle proteinopathies

Prajwal Ciryam, Matthew Antalek, Fernando Cid, Gian Gaetano Tartaglia, Christopher M. Dobson, Anne Katrin Guettsches, Britta Eggers, Matthias Vorgerd, Katrin Marcus, Rudolf A. Kley, Richard I. Morimoto, Michele Vendruscolo, Conrad C. Weihl*

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number197
JournalActa Neuropathologica Communications
Volume7
Issue number1
DOIs
StatePublished - Dec 3 2019

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Ciryam, P., Antalek, M., Cid, F., Tartaglia, G. G., Dobson, C. M., Guettsches, A. K., Eggers, B., Vorgerd, M., Marcus, K., Kley, R. A., Morimoto, R. I., Vendruscolo, M., & Weihl, C. C. (2019). A metastable subproteome underlies inclusion formation in muscle proteinopathies. Acta Neuropathologica Communications, 7(1), [197]. https://doi.org/10.1186/s40478-019-0853-9