Pathogenic role of valosin-containing protein (VCP) in IBMPFD

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Mutations in valosin-containing prote in (VCP) cause a rare complex disorder called inclusion body myopathy associated with Paget disease ofthe bone and frontotemporal dementia (IBMPFD). The exact underlying molecular and cellular pathogenic a nd degenerative mechanisms mediated by mutant VCP remain unl<nown. Quite recently, mutations in VCP have also been found patients in amyotrophic lateral sclerosis (ALS). collectively suggesting that dysruptions of physiological functions of VCP significantly impact various cell lineages and tissues, and these changes may be mediated by shared pathological mechanisms. This has been the rationale for our longstanding objective in neurodegenerative and muscular degenerative disorders. Therefore, establishing in vitro and in vivo models ofthis complex disease is a critical first step for elucidating the cellular- and molecular-based pathogenic processes triggered by a disease-relevant mutant VCP and will help developing potential therapeutic strategies for this devastating disorder. Our preliminary data as well as clinical observations suggest mutant VCP mediates an impairment of protein degradation processes and results in accumulations of protein aggregates in affected cells. In this proposal, we hypothesize that VCP regulates autophagy and . In Aim 1, we will investigate the underlying molecular mechanisms by which mutant VCP impairs autophagy in cell culture models, and how these impairments impact on protein accumulations and innate inflammatory responses. In Aim 2, we will generate a novel induci ble transgenic mouse harboring a clinical mutation in the VCP gene as a model for IBMPFD. This transgenic model will provide insight into the m olecular mechanisms of the disease, and will serve as a valuable tool for preclinical therapeutic interventions. The inducible VCP mouse model is significant for the field and offers several distinct and significant advantages: (1) it is only one of a few models for IBMPFD; (2) mutant VCP expression can not only be limited to specific tissue(s) based on the research interest, but also be turn on and off during the lifespan of the mouse; and (3) by limiting mutant VCP expression, we are able to avoid confounding complications. We believe that our proposed pr eject will advance our understandin gs in IBMPFD and related VCP diseases and help developing effective therapies.