Rare genetic causes of human disease have the potential to reveal mechanistic insights into more common sporadic disease. Tauopathies are a group of fatal neurologic diseases, including Alzheimer's disease, where dementia and neurodegeneration are the result of accumulation of pathologic tau protein aggregates in the form of neurofibrillary tangles, Pick bodies, or glial inclusions. We have identified a novel autosomal dominant form of frontotemporal dementia with tau inclusions associated with a novel hypomorphic genetic mutation in VCP which may be linked to a loss of anti-tau disaggregase activity. However, hypermorphic VCP mutations cause a distinct disease called multisystem proteinopathy which can manifest as frontotemporal lobar degeneration with TDP-43 inclusions. We propose three specific aims to understand the basic molecular mechanisms by which this gene mutation leads to diverse pathologies. We will perform structural biology studies to better understand how VCP protein interacts with pathologic protein aggregates, and how VCP mutations affect disaggregase activity. We will extend these studies into cellular/neuronal VCP knock-in models to determine how VCP mutations affect cellular VCP activity within a cellular context. Finally, we will determine whether gains or losses of VCP activity can modify tau toxicity in vivo. Together, these mechanistic studies will elucidate basic mechanisms by which VCP dysfunction leads to different types of proteinopathy, providing the basis for future novel anti-tau therapies based on modulating VCP activity.