FOR 1228:  Molecular Pathogenesis of Myofibrillar Myopathies

• Subject Area: Medicine
• Term: from 2009 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 101925924

Myofibrillar myopathies are progressive and devastating diseases of the human skeletal muscle that often lead to premature death. To date, no causative or ameliorating therapy is available. Myofibrillar myopathies are histopathologically characterised by pathological protein aggregates and degenerative changes of myofibrills. While half of these progressive muscle diseases are caused by desmin-, filamin C-, plectin-, VCP-, FHL1-, ZASP-, myotilin-, ?B-crystallin and BAG3-gene mutations, the other half of Myofibrillar myopathies is due to still unresolved gene defects. The precise molecular pathways leading from an individual gene defect to a mutually shared structural pathology of skeletal muscle tissue are currently unknown. This Research Unit focusses on the following goals: (1) characterisation of individual and shared disease mechanisms in myofibrillar myopathies due to desmin-, plectin-, filamin C-, ZASP-, VCP-, FHL1- and ?B-crystallin mutations; (2) systematic analyses of disease-specific cell and animal models; (3) validation of cell and animal models for pharmacological treatment strategies; (4) biochemical characterisation of the composition of pathological protein aggregates in skeletal muscle biopsies from patients with myofibrillar myopathies and disease relevant animal models; (5) identification of novel genes and proteins that are centrally involved in the pathogenesis of myofibrillar myopathies. This Research Unit, which is driven by distinguished groups from eight different universities, will specifically analyse the pathogenesis of myofibrillar myopathies. This work will be the basis for novel targeted treatment approaches for this significant cohort of hereditary myopathies.

• DFG Programme: Research Units
• International Connection: Austria

Projects

• Analysis of in vivo consequences of disease-relvant point mutations in p97 (VCP) in Dictostelium discoideum, a simple and powerful model system for functional genomics (Applicant Eichinger, Ludwig )
• Biochmechanics of MFM: a multi-scale approach (Applicants Fabry, Ben ;  Friedrich, Oliver ;  Pfitzer, Gabriele )
• Central Protein Analysis (Applicant Hanisch, Franz-Georg )
• Coordination project (Applicant Schröder, Rolf )
• Desmin cardiac myopathy: molecular pathogenesis and novel treatment concepts (Applicants Clemen, Christoph S. ;  Müller, Oliver J. ;  Schröder, Rolf )
• FHL1-related reducing-body myopathy and other genetic forms of myofibrillar myopathies: composition of pathological protein aggregates revealed by laser capture microdissection and subsequent proteomic analysis (Applicants Kress, Wolfram ;  Schessl, Joachim )
• Filamin C myopathy: from pathogenic mutations towards novel targeted treatment concepts (Applicants Fürst, Dieter O. ;  Kley, Rudolf Andre )
• Functional genomics in zebrafish to disset the pathogenesis of myofibrillar myopathies (Applicants Just, Steffen ;  Rottbauer, Wolfgang )
• Identification of novel and disease-related VCP/p97 binding partners and effects of disease-causing VCP/p97 mutations on protein interactions and protein quality control systems in Dictyostelium and mouse (Applicants Clemen, Christoph S. ;  Eichinger, Ludwig ;  Schröder, Rolf )
• Impact of MFM disease mutations on the assembly mechanism and network formation of muscle-specific intermediate filament proteins (Applicant Herrmann, Harald )
• Knockout mice and myocyte cell models to study the pathogenesesis and phenotype rescue of muscular plectinopathies (Applicant Wiche, Gerhard )
• Scanning for intensely fluorescent targets (SIFT): a new tool to study pathological protein aggregate formation in MFM and its reversal through pharmacologic intervention (Applicant Walter, Maggie C. )

• Spokesperson: Professor Dr. Rolf Schröder