title: Impairment of protein degradation in myofibrillar myopathy caused by FLNC/filamin C mutations.
abstract: Myofibrillar myopathy caused by FLNC/filamin C mutations is characterized by disintegration of myofibrils and a massive formation of protein aggregates within skeletal muscle fibers. We performed immunofluorescence studies in skeletal muscle sections from filaminopathy patients to detect disturbances of protein quality control mechanisms. Our analyses revealed altered expression of chaperone proteins and components of proteasomal and autophagic degradation pathways in abnormal muscle fibers that harbor protein deposits but not in neighboring muscle fibers without pathological protein aggregation. These findings suggest a dysfunction of protein stabilizing and degrading mechanisms that leads to a pathological accumulation of protein aggregates in abnormal fibers. Accordingly, a pharmacological modulation of chaperone activity may be a promising therapeutic strategy to prevent protein aggregation and to reduce disease progression. Newly established filaminopathy cell culture models provide a suitable basis for testing such pharmacological approaches.
authors.affiliation: Department of Neurology, Neuromuscular Center Ruhrgebiet, University Hospital Bergmannsheil, Ruhr-University, Bochum, Germany. rudolf.kley@rub.de
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: Kley
authors.forename: Peter F M
authors.initials: PF
authors.lastname: van der Ven
authors.forename: Montse
authors.initials: M
authors.lastname: Olivé
authors.forename: Jörg
authors.initials: J
authors.lastname: Höhfeld
authors.forename: Lev G
authors.initials: LG
authors.lastname: Goldfarb
authors.forename: Dieter O
authors.initials: DO
authors.lastname: Fürst
authors.forename: Matthias
authors.initials: M
authors.lastname: Vorgerd
mesh_terms: D002478:Cells, Cultured; D003285:Contractile Proteins / Q000235:genetics*; D064448:Filamins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics*; D018832:Molecular Chaperones / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009210:Myofibrils / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D003285:Contractile Proteins; C578661:FLNC protein, human; D064448:Filamins; D006360:Heat-Shock Proteins; D008840:Microfilament Proteins; D018832:Molecular Chaperones; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex