Advisory Committee Chair
Erik Roberson
Advisory Committee Members
Andrew Arrant
Paul D Gamlin
Ashley Harms
Jennifer Pollack
Elizabeth S Sztul
Document Type
Dissertation
Date of Award
2023
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
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.
Recommended Citation
Kashyap, Shreya Natesh, "Optimization of Progranulin Gene Therapy, a Potential Treatment for Frontotemporal Dementia" (2023). All ETDs from UAB. 422.
https://digitalcommons.library.uab.edu/etd-collection/422