Clemen, Christoph S., Stoeckigt, Florian, Strucksberg, Karl-Heinz, Chevessier, Frederic, Winter, Lilli ORCID: 0000-0002-6368-1160, Schuetz, Johanna, Bauer, Ralf, Thorweihe, Jose-Manuel, Wenzel, Daniela ORCID: 0000-0003-1100-6363, Schloetzer-Schrehardt, Ursula, Rasche, Volker, Krsmanovic, Pavle ORCID: 0000-0003-1142-4282, Katus, Hugo A., Rottbauer, Wolfgang, Just, Steffen, Mueller, Oliver J., Friedrich, Oliver ORCID: 0000-0003-2238-2049, Meyer, Rainer, Herrmann, Harald, Schrickel, Jan Wilko and Schroeder, Rolf (2015). The toxic effect of R350P mutant desmin in striated muscle of man and mouse. Acta Neuropathol., 129 (2). S. 297 - 316. NEW YORK: SPRINGER. ISSN 1432-0533

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Clemen, Christoph S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoeckigt, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strucksberg, Karl-HeinzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chevessier, FredericUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winter, LilliUNSPECIFIEDorcid.org/0000-0002-6368-1160UNSPECIFIED
Schuetz, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bauer, RalfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thorweihe, Jose-ManuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wenzel, DanielaUNSPECIFIEDorcid.org/0000-0003-1100-6363UNSPECIFIED
Schloetzer-Schrehardt, UrsulaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rasche, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krsmanovic, PavleUNSPECIFIEDorcid.org/0000-0003-1142-4282UNSPECIFIED
Katus, Hugo A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rottbauer, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Just, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, Oliver J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Friedrich, OliverUNSPECIFIEDorcid.org/0000-0003-2238-2049UNSPECIFIED
Meyer, RainerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herrmann, HaraldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schrickel, Jan WilkoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeder, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-413554
DOI: 10.1007/s00401-014-1363-2
Journal or Publication Title: Acta Neuropathol.
Volume: 129
Number: 2
Page Range: S. 297 - 316
Date: 2015
Publisher: SPRINGER
Place of Publication: NEW YORK
ISSN: 1432-0533
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MICE LACKING DESMIN; VENTRICULAR-TACHYCARDIA; INTERMEDIATE-FILAMENTS; DILATED CARDIOMYOPATHY; SKELETAL MYOPATHY; WILD-TYPE; IN-VITRO; GENE; CYCLOHEXIMIDE; DISEASESMultiple languages
Clinical Neurology; Neurosciences; PathologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/41355

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