Funded by the National Institute on Aging, the 2-year project entitled, “Protein homeostasis in a frontotemporal dementia iPSC model,” was granted to McGowan Institute for Regenerative Medicine affiliated faculty member Charleen Chu, MD, PhD (pictured), the A. Julio Martinez Chair in Neuropathology in the Department of Pathology, University of Pittsburgh School of Medicine. The project began on August 1, 2022.
The valosin-containing protein (VCP) functions as a regulatory hub for multiple facets of protein homeostasis. Mutations in VCP cause familial neurodegeneration with features of frontotemporal dementia and musculoskeletal disease. Dr. Chu’s team will create new pluripotent cellular models derived from patient fibroblasts to study which of the major VCP functions are altered by a disease-causing mutation in human brain cells.
The project abstract reads:
Maintaining protein homeostasis is a particular challenge for neurons, in which a high demand for protein synthesis, folding and transport represents a constant source of stress. Evidence of protein mishandling is observed in nearly all neurodegenerative diseases including the AD-related dementias (ADRD). The AAA-ATPase valosin-containing protein (VCP) plays a central role in maintaining multiple aspects of protein homeostasis. Mutations in VCP have been linked to several forms of frontotemporal lobar degeneration with or without concurrent motor dysfunction and musculoskeletal disease. Yet there is limited understanding of how these mutations affect different aspects of VCP function in neurons. The VCP-T262A mutation causes familial frontotemporal dementia with aphasia and parkinsonism. Preliminary studies in primary neurons transfected with VCP-T262A reveal deficits in dendritic arborization, and patient fibroblasts bearing the endogenous mutation exhibit disrupted secretory function. Reagents to create human neurons and other relevant cell types bearing the endogenous VCP-T262A mutation are critically needed to study pathophysiological mechanisms of disease. In this exploratory project, we will create isogenic pairs of iPSC lines expressing T262A vs. wild type VCP. We will differentiate to cortical neurons to study the effects of this mutation upon ER stress, autophagy and Golgi markers compared to iPSC-derived cells with a mutation in a different VCP functional domain. Our long-range goals are to understand how alterations in VCP contribute to synaptic loss so that this mechanistic understanding can be translated into new therapeutic approaches.
Congratulations, Dr. Chu!
NIH Reporter: Protein homeostasis in a frontotemporal dementia iPSC model