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

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Mutations of the human VCP/p97 gene cause autosomal dominant "Inclusion Body Myopathy with early-onset Paget disease of bone and Frontotemporal Dementia" (IBMPFD) and an "amyotrophic lateral sclerosis" (ALS) variant. In the first funding period, we generated and characterized a series of VCP/p97 mutant Dictyostelium strains, characterized a VCP/p97 haploinsufficient mouse model and identified and characterized novel and disease-relevant VCP/p97 binding partners. In the proposed work program for the second funding period, we will extend our studies on VCP/p97 with particular emphasis on the molecular basis of IBMPFD, employing a broad spectrum of experimental procedures ranging from biochemical and molecular biology experiments, cell biological assays using mammalian and Dictyostelium cells to mouse models. We will identify further novel VCP/p97 binding partners, explore the molecular interactions within VCP/p97 protein complexes and analyze expression changes in autophagy components. We will elucidate functional consequences of R155C mutant VCP/p97 in Dictyostelium strains with respect to proteasomal activity, autophagy flux, and the composition of protein aggregates. Corresponding experiments as well as a detailed characterization of the skeletal muscle pathology will be carried out in our newly generated R155C VCP/p97 knock-in mouse model.