期刊
ACTA NEUROPATHOLOGICA
卷 129, 期 2, 页码 297-315出版社
SPRINGER
DOI: 10.1007/s00401-014-1363-2
关键词
Desminopathy; R350P desmin missense mutation; Desmin knock-in mouse; Mouse model; Mutant desmin; Intermediate filament; Extrasarcomeric intermediate filament network; Mechanical vulnerability; Protein aggregation myopathy; Skeletal muscle weakness; Protein aggregation cardiomyopathy; Cardiac arrhythmia; Cardiac conduction defect
资金
- German Research Foundation (DFG) [FOR1228, CL 381/7-1, MU 1654/8-1, HE 1853/9-2, SCHR 562/13-1]
- German ministry of education and research (BMBF)
- Deutsche Gesellschaft fur Muskelkranke e.V. (DGM)
- Johannes and Frieda Marohn Stiftung
- German Cardiac Society (DGK Stipendium)
- Medical Faculty Dean's teaching and research investment funds
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.
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