Schuld, Julia, Orfanos, Zacharias, Chevessier, Frederic, Eggers, Britta ORCID: 0000-0002-6553-4631, Heil, Lorena, Uszkoreit, Julian, Unger, Andreas, Kirfel, Gregor, van der Ven, Peter F. M., Marcus, Katrin, Linke, Wolfgang A., Clemen, Christoph S., Schroeder, Rolf and Fuerst, Dieter O. (2020). Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation. Acta Neuropathol. Commun., 8 (1). LONDON: BMC. ISSN 2051-5960

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Abstract

Filamin C (FLNc) is mainly expressed in striated muscle cells where it localizes to Z-discs, myotendinous junctions and intercalated discs. Recent studies have revealed numerous mutations in theFLNCgene causing familial and sporadic myopathies and cardiomyopathies with marked clinical variability. The most frequent myopathic mutation, p.W2710X, which is associated with myofibrillar myopathy, deletes the carboxy-terminal 16 amino acids from FLNc and abolishes the dimerization property of Ig-like domain 24. We previously characterized knock-in mice heterozygous for this mutation (p.W2711X), and have now investigated homozygous mice using protein and mRNA expression analyses, mass spectrometry, and extensive immunolocalization and ultrastructural studies. Although the latter mice display a relatively mild myopathy under normal conditions, our analyses identified major mechanisms causing the pathophysiology of this disease: in comparison to wildtype animals (i) the expression level of FLNc protein is drastically reduced; (ii) mutant FLNc is relocalized from Z-discs to particularly mechanically strained parts of muscle cells, i.e. myotendinous junctions and myofibrillar lesions; (iii) the number of lesions is greatly increased and these lesions lack Bcl2-associated athanogene 3 (BAG3) protein; (iv) the expression of heat shock protein beta-7 (HSPB7) is almost completely abolished. These findings indicate grave disturbances of BAG3-dependent and -independent autophagy pathways that are required for efficient lesion repair. In addition, our studies reveal general mechanisms of lesion formation and demonstrate that defective FLNc dimerization via its carboxy-terminal domain does not disturb assembly and basic function of myofibrils. An alternative, more amino-terminally located dimerization site might compensate for that loss. Since filamins function as stress sensors, our data further substantiate that FLNc is important for mechanosensing in the context of Z-disc stabilization and maintenance.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schuld, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Orfanos, ZachariasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chevessier, FredericUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eggers, BrittaUNSPECIFIEDorcid.org/0000-0002-6553-4631UNSPECIFIED
Heil, LorenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uszkoreit, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Unger, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kirfel, GregorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Ven, Peter F. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marcus, KatrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Linke, Wolfgang A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clemen, Christoph S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeder, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fuerst, Dieter O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-319759
DOI: 10.1186/s40478-020-01001-9
Journal or Publication Title: Acta Neuropathol. Commun.
Volume: 8
Number: 1
Date: 2020
Publisher: BMC
Place of Publication: LONDON
ISSN: 2051-5960
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
IMMUNOELECTRON MICROSCOPY; PROTEIN AGGREGATION; ACTIN NETWORKS; IN-VITRO; Z-DISC; FLNC; XIN; INTERACTS; BINDING; DOMAINMultiple languages
NeurosciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/31975

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