FOR 1228: Molecular Pathogenesis of Myofibrillar Myopathies

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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.