Advisory Committee Chair
Advisory Committee Members
Paul D Gamlin
Elizabeth S Sztul
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) School of Medicine
Heterozygous loss of function mutations in the progranulin gene cause frontotemporal dementia, characterized by deficits in social behavior, language comprehension and motor function. Almost every frontotemporal dementia-related progranulin mutation is loss of function and results in progranulin haploinsufficiency. For this reason, progranulin replacement is a conceptually straightforward therapeutic strategy for patients with frontotemporal dementia caused by progranulin mutations. Here, we outline progranulin biology, progranulin deficient mouse models of frontotemporal dementia and preclinical interventions centered around increasing brain progranulin levels. We have demonstrated that blocking the progranulin C-terminus, which harbors the sortilin binding site, improves the cross-correctional capacity of neurotropic progranulin gene therapy to correct microglial phenotypes of progranulin deficiency. We have also characterized the impact of progranulin deficiency on microglial lipofuscinosis, a potential outcome measure for future preclinical studies of progranulin boosting interventions. Altogether, this dissertation provides both a novel therapeutic approach to boost brain progranulin, and a better understanding of the natural history of cell types specific changes in the progranulin deficient brain.
Kashyap, Shreya Natesh, "Optimization of Progranulin Gene Therapy, a Potential Treatment for Frontotemporal Dementia" (2023). All ETDs from UAB. 422.
Available for download on Monday, September 01, 2025