Valosin-containing protein (VCP) variants cause multisystem proteinopathy (MSP), a disease characterized by multiple clinical phenotypes including inclusion body myopathy (IBM), Paget’s disease of the bone (PDB), and frontotemporal dementia (FTD). VCP is a member of the AAA+ superfamily of proteins that utilizes energy derived from ATP hydrolysis to carry out segregase function including extracting proteins out from membranes and dissociating apart macromolecule structures. In this dissertation, we explore how VCP variants lead to a loss of VCP function, causes defects in protein homeostasis, and promotes disease progression. In Chapter 2, we provide evidence that the three distinct cell types affected in MSP share a common pathologic feature, the presence of ubiquitinated intranuclear inclusions. We find that in CRISPR/cas9 knock-in HeLa cells expressing pathogenic MSP-VCP variants, nuclear VCP expression is reduced. We also generate a nuclear TDP-43 aggregation model using a RNA deficient TDP-43 construct (TDP-4FL) that when expressed in cells, form large and insoluble inclusions under proteasomal inhibition. When TDP-4FL is expressed in MSP-VCP variant cell lines or when VCP is pharmacologically inhibited, clearance of TDP-4FL aggregates is decreased. Furthermore, we identify four novel VCP activators which increase VCP’s activity primarily through its D2 ATPase domain. When cells are treated with the most active compound, clearance of TDP-43 aggregates are enhanced in wild-type cells and cells expressing MSP-VCP variants. In Chapter 3, we identify and describe a novel VCP variant, VCP D395G, that leads to FTD and is associated with tau pathology and aberrant neuronal vacuole structures. We demonstrate that D395G mutation differs from MSP-VCP variants in that it leads to a reduction in ATPase activity. This decrease in ATPase activity is correlated with a decrease in tau disaggregase activity in vitro, and enhanced tau aggregation in cells. Lastly, intracerebral microinjection of human-derived AD tau lysates into CRISPR-edited mice expressing VCP-D395G led to worsen tau pathology. In sum, these studies highlight two novel loss of function mechanism driven by VCP variants and we posit that increasing VCP activity could enhance clearance of protein aggregation in the setting of neurodegeneration.