Cellular mechanisms leading to desminopathy: Segregation, aggregation and proteostasis imbalance of desmin mutants in muscle cells and tissue
Final Report Abstract
A major outcome of this study is the direct and strong binding of the unconventional intermediate filament protein syncoilin to desmin. Its orininal description was in muscle, where it was found to localize to desmin filaments at the sites of their association with costameres. In addition, the direct interaction with a second unconventional intermediate filament protein, nestin, was identified, which has also repeatedly reported to localize with IFs in the past, but now we have evidence that they already interact, within a small complexes, in situ. Notably, these interactions occur both in an artificial cell system, vimentin-knockout fibroblasts expressing desmin, as well as in myoblasts from knock-in mice. At present, we do not know if these interactions help to chaperone the folding of desmin into functional coiled coils and eventual mediate loading of unit-length-filaments to structural hubs for transport in further topological processing. This possibility has to be investigated within the next future. Furthermore, we have not observed major differences in the composition of the desmincomplexes between WT-desmin and mutant desmin expressing cells yet, although some of the factors captured uniquely need further investigation.
Publications
- (2017) Early signs of architectural and biomechanical failure in isolated myofibers and immortalized myoblasts from desminmutant knock-in mice. Sci Rep. 7, 1391
Diermeier S, Iberl J, Vetter K, Haug M, Pollmann C, Reischl B, Buttgereit A, Schürmann S, Spörrer M, Goldmann WH, Fabry B, Elhamine F, Stehle R, Pfitzer G, Winter L, Clemen CS, Herrmann H, Schröder R, Friedrich O
(See online at https://doi.org/10.1038/s41598-017-01485-x) - (2018) Assembly kinetics of vimentin tetramers to unit-length filaments: A stopped-flow study. Biophys. J. 114, 2408–2418
Mücke N, Kämmerer L, Winheim S, Kirmse R, Krieger J, Mildenberger M, Baßler J, Hurt E, Goldmann WH, Aebi U, Toth K, Langowski J, Herrmann H
(See online at https://doi.org/10.1016/j.bpj.2018.04.032) - (2019) Imbalances in protein homeostasis caused by mutant desmin. Neuropathol. Appl. Neurobiol. 45, 476-494
Winter L, Unger A, Berwanger C, Spörrer M, Türk M, Chevessier F, Strucksberg KH, Schlötzer- Schrehard U, Wittig I, Goldmann WH, Marcus K, Linke WA, Clemen CS, Schröder R
(See online at https://doi.org/10.1111/nan.12516) - (2019) The MyoRobot technology discloses a premature biomechanical decay of skeletal muscle fiber bundles derived from R349P desminopathy mice. Sci Rep. 9,10769
Haug M, Meyer C, Reischl B, Prölß G, Vetter K, Iberl J, Nübler S, Schürmann S, Rupitsch SJ, Heckel M, Pöschel T, Winter L, Herrmann H, Clemen CS, Schröder R, Friedrich O
(See online at https://doi.org/10.1038/s41598-019-46723-6) - (2020) Dual Functional States of R406W-Desmin Assembly Complexes Cause Cardiomyopathy with Severe Intercalated Disc Derangement in Humans and in Knock-In Mice. Circulation 142, 2155-2171
Herrmann H, Cabet E, Chevalier NR, Moosmann J, Schultheis D, Haas J, Schowalter M, Berwanger C, Weyerer V, Agaimy A, Meder B, Müller OJ, Katus HA, Schlötzer- Schrehardt U, Vicart P, Ferreiro A, Dittrich S, Clemen CS, Lilienbaum A, Schröder R
(See online at https://doi.org/10.1161/CIRCULATIONAHA.120.050218) - (2021) Effects of vimentin intermediate filaments on the structure and dynamics of in vitro multicomponent interpenetrating cytoskeletal networks. Phys. Rev. Lett.
Shen Y, Wu H, Lu PJ, Wang D, Shayegan M, Li H, Shi W, Wang Z, Cai L-H, Xia J, Zhang M, Ding R, Herrmann H, Goldman R, MacKintosh FC, Moncho-Jordá A, Weitz DA
(See online at https://doi.org/10.1103/PhysRevLett.127.108101) - (2021) New roles for desmin in the maintenance of muscle homeostasis. FEBS J. Apr 7
Agnetti G, Herrmann H, Cohen S.
(See online at https://doi.org/10.1111/febs.15864)
