Universität zu Köln

Winter, L., Unger, A., Berwanger, C., Spoerrer, M., Tuerk, M., Chevessier, F., Strucksberg, K. -H., Schloetzer-Schrehardt, U., Wittig, I., Goldmann, W. H., Marcus, K., Linke, W. A., Clemen, C. S. and Schroeder, R. (2019). Imbalances in protein homeostasis caused by mutant desmin. Neuropathol. Appl. Neurobiol., 45 (5). S. 476 - 495. HOBOKEN: WILEY. ISSN 1365-2990

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Abstract

Aims We investigated newly generated immortalized heterozygous and homozygous R349P desmin knock-in myoblasts in conjunction with the corresponding desminopathy mice as models for desminopathies to analyse major protein quality control processes in response to the presence of R349P mutant desmin. Methods We used hetero- and homozygous R349P desmin knock-in mice for analyses and for crossbreeding with p53 knock-out mice to generate immortalized R349P desmin knock-in skeletal muscle myoblasts and myotubes. Skeletal muscle sections and cultured muscle cells were investigated by indirect immunofluorescence microscopy, proteasomal activity measurements and immunoblotting addressing autophagy rate, chaperone-assisted selective autophagy and heat shock protein levels. Muscle sections were further analysed by transmission and immunogold electron microscopy. Results We demonstrate that mutant desmin (i) increases proteasomal activity, (ii) stimulates macroautophagy, (iii) dysregulates the chaperone assisted selective autophagy and (iv) elevates the protein levels of alpha B-crystallin and Hsp27. Both alpha B-crystallin and Hsp27 as well as Hsp90 displayed translocation patterns from Z-discs as well as Z-I junctions, respectively, to the level of sarcomeric I-bands in dominant and recessive desminopathies. Conclusions Our findings demonstrate that the presence of R349P mutant desmin causes a general imbalance in skeletal muscle protein homeostasis via aberrant activity of all major protein quality control systems. The augmented activity of these systems and the subcellular shift of essential heat shock proteins may deleteriously contribute to the previously observed increased turnover of desmin itself and desmin-binding partners, which triggers progressive dysfunction of the extrasarcomeric cytoskeleton and the myofibrillar apparatus in the course of the development of desminopathies.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Winter, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Unger, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Berwanger, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Spoerrer, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tuerk, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chevessier, F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Strucksberg, K. -H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schloetzer-Schrehardt, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wittig, I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Goldmann, W. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Marcus, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Linke, W. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Clemen, C. S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeder, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-134145
DOI:	10.1111/nan.12516
Journal or Publication Title:	Neuropathol. Appl. Neurobiol.
Volume:	45
Number:	5
Page Range:	S. 476 - 495
Date:	2019
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1365-2990
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language UBIQUITIN-PROTEASOME SYSTEM; ALPHA-B-CRYSTALLIN; SKELETAL-MUSCLE; INTERMEDIATE-FILAMENTS; MUSCULAR-DYSTROPHY; AUTOPHAGY; AGGREGATION; CHAPERONE; MYOPATHY; PATHOLOGY Multiple languages Clinical Neurology; Neurosciences; Pathology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13414