Filamin C myopathy: from pathogenic mutations towards novel targeted treatment concepts

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Filamin C-related myopathies delineate diseases caused by mutations in the FLNC gene. Beyond the first descriptions of human FLNC mutations, we have provided comprehensive analyses of associated myopathological characteristics and biochemical pathomechanisms. The first major goal of the proposed project is to obtain deeper insight into the pathological consequences of FLNC mutations and to test therapeutic approaches based on results of the first funding period. To address this issue we will characterize newly identified aggregate components and filamin C ligands in the context of their disease involvement and evaluate effects of chaperone-inducing agents on aggregate formation in cell culture models of filaminopathy. These studies will be complemented by investigations of signalling pathways at the cellular level, with an emphasis on selective autophagic protein degradation. The second main aim is to decipher the composition of protein aggregates in MFM to get new insights in pathomechanisms. To achieve this goal we will extend our proteomic analysis successfully performed in filaminopathy to additional genetically clarified MFM subtypes and compare the results with other protein aggregate myopathies.