Frontotemporal lobar degeneration (FTLD) encompasses a heterogeneous group of clinical syndromes that include frontotemporal dementia, frontotemporal dementia with motor neuron disease, progressive non-fluent aphasia, semantic dementia and progressive apraxia. Both sporadic and familial forms exist. We are investigating a rare form of FTLD called frontotemporal dementia with inclusion body myopathy and Paget's disease of bone (IBMPFD). This is an autosomal dominant disorder caused by mutations in the gene valosin-containing protein (VCP). The CNS pathology is characterized by prominent ubiquitin-positive inclusions that also stain for TAR DNA binding protein (TDP43), a feature that links this rare disease with the majority of sporadic FTD as well as FTD resulting from other genetic mutations. We are examining the molecular pathogenesis of mutant VCP-dependent neurodegeneration in Drosophila and mouse model systems.