Dysregulation of p97/VCP disease mutants in IBM and FTLD-U

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Many neurodegenerative diseases are thought to be caused by a buildup of toxic proteins in the brain from or resulting in promotion of apoptosis. p97 AAA ATPase (also known as VCP, CDC48, TER ATPase) functions in multiple biological processes, targeting proteins to 2 major degradation systems, the proteasome and autophagy machinery. The key role of p97 in proteasome and autophagy degradations underscores its importance and supports involvement of p97 dysregulation in protein misfolding, aggregation, and processing errors, eventually resulting in cell death. Single amino acid mutations in p97/VCP cause autosomal dominant human disorders including hereditary frontotemporal dementia hereditary (FTD) and a specific condition called inclusion body myopathy with Paget disease of the bone plus ALS, a motor neuron disease also known as Lou Gehrig's disease. Mutation sources could be genetic, environmental, spontaneous, or age related. The goal of this project is to identify key pathogenic mechanisms that will be used to develop precision therapy to correct the defect due to p97 disease mutations, without damaging normal p97 functions. Our central hypothesis: p97 disease mutants have abnormal conformation, which in turn leads to altered protein interactome that in specific cells including neuronal cells cause pathogenic effect To test this hypothesis and to identify key pathogenic mechanisms that can act as targets for therapeutic intervention, we propose to compare the interactome of WT and disease mutants of p97 in neuronal and muscle cells derived from patient fibroblasts and then use genetic and biochemical approaches to determine the effect of the altered interactors in regulating p97 ATPase activity and in modulating the disease phenotype. Overall, a new paradigm of how to develop mutant-targeted therapeutics for neurodegenerative diseases—especially for causative mutants in the ATPase protein family— will be established.