The toxic effect of R350P mutant desmin in striated muscle of man and mouse.

Clemen C, Stöckigt F, Strucksberg KH, Chevessier F, Winter L, Schütz J, Bauer R, Thorweihe JM, Wenzel D, Schlötzer-Schrehardt U, Rasche V, Krsmanovic P, Katus H, Rottbauer W, Just S, Müller OJ, Friedrich O, Meyer R, Herrmann H, Schrickel JW, Schröder R (2015)

Publication Language: English

Publication Status: Published

Publication Type: Journal article, Original article

Publication year: 2015

Journal

Acta Neuropathologica Springer

Book Volume: 129

Pages Range: 297-315

Journal Issue: 2

URI: http://link.springer.com/article/10.1007%2Fs00401-014-1363-2

DOI: 10.1007/s00401-014-1363-2

Open Access Link: http://link.springer.com/article/10.1007%2Fs00401-014-1363-2

Abstract

Mutations of the human desmin gene on chromosome 2q35 cause autosomal dominant, autosomal recessive and sporadic forms of protein aggregation myopathies and cardiomyopathies. We generated R349P desmin knock-in mice, which harbor the ortholog of the most frequently occurring human desmin missense mutation R350P. These mice develop age-dependent desmin-positive protein aggregation pathology, skeletal muscle weakness, dilated cardiomyopathy, as well as cardiac arrhythmias and conduction defects. For the first time, we report the expression level and subcellular distribution of mutant versus wild-type desmin in our mouse model as well as in skeletal muscle specimens derived from human R350P desminopathies. Furthermore, we demonstrate that the missense-mutant desmin inflicts changes of the subcellular localization and turnover of desmin itself and of direct desmin-binding partners. Our findings unveil a novel principle of pathogenesis, in which not the presence of protein aggregates, but disruption of the extrasarcomeric intermediate filament network leads to increased mechanical vulnerability of muscle fibers. These structural defects elicited at the myofiber level finally impact the entire organ and subsequently cause myopathy and cardiomyopathy.

Authors with CRIS profile

Ursula Schlötzer-Schrehardt Medizinische Fakultät Oliver Friedrich Lehrstuhl für Medizinische Biotechnologie Rolf Schröder Professur für Neuropathologie

Related research project(s)

Biochmechanics of MFM: a multi-scale approach FOR 1228: Molecular Pathogenesis of Myofibrillar Myopathies Oct. 1, 2012 - March 31, 2016 Biomechanical changes of skeletal muscle in desminopathies - a novel approach to unravel the causes of progressive weakness in inherited muscle diseases July 1, 2014 - June 30, 2015

Involved external institutions

Universität zu Köln DE Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Universitätsklinikum Ulm DE Germany (DE) Universitätsklinikum Bonn DE Germany (DE) Universitätsklinikum Heidelberg DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE)

How to cite

APA:

Clemen, C., Stöckigt, F., Strucksberg, K.-H., Chevessier, F., Winter, L., Schütz, J.,... Schröder, R. (2015). The toxic effect of R350P mutant desmin in striated muscle of man and mouse. Acta Neuropathologica, 129(2), 297-315. https://doi.org/10.1007/s00401-014-1363-2

MLA:

Clemen, Christoph, et al. "The toxic effect of R350P mutant desmin in striated muscle of man and mouse." Acta Neuropathologica 129.2 (2015): 297-315.

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