Progranulin is a widely expressed, secreted glycoprotein, originally discovered for its growth factor-like properties, and later identified as causative gene for frontotemporal dementia, a devastating neurodegenerative disease with no cure. Progranulin is also implicated in other diseases including cancer, obesity, diabetes, atherosclerosis, arthritis, and neuronal ceroid lipofuscinosis. Thus, a better understanding of progranulin biology has widespread significance for human health and disease. Consistent with its links to multiple diseases, progranulin participates in a multitude of physiological processes including cell survival, tumor cell growth, vascularization, neurite outgrowth, inflammation and insulin signaling. Yet, fundamental questions regarding progranulin biochemistry and function remain unanswered. What is its bioactive form- progranulin or granulin(s)? How does progranulin's structure affect its activity? Does cleavage affect progranulin activity? I propose t focus on these biochemical aspects of progranulin's activity and structure. Using cell-based functional assays, I will define the region(s) of progranulin which are bioactive and test if cleavage of progranulin into smaller granulin domains is required for activity. I hypothesize that full-length progranulin is a pro-protein which does not possess bioactivity and that the cleaved granulins fragments are the major bioactive species. Additionally, I will extend my recent finding that progranulin exists as homodimers by elucidating the mechanism underlying progranulin dimerization and determining its functional significance. Finally, I will test the potential utilit of nonsense-mediated mRNA decay inhibition as a therapeutic strategy for treating frontotemporal dementia. Using patient-relevant models, I will test if this strategy can restore expression of truncated progranulin and, thus, progranulin function. Completion of these studies will significantly advance our understanding of progranulin's activity and biochemical nature. This fundamental knowledge will provide a biochemical framework for future studies aimed at understanding progranulin's precise function and may shed light on how progranulin mutations cause frontotemporal dementia. Moreover, these studies will provide initial insights about the potential utility of a novel therapeutic approach for treating progranulin-deficient forms of frontotemporal dementia.

Public Health Relevance

Progranulin is a widely expressed protein with many ascribed functions that is implicated in frontotemporal dementia, a devastating neurodegenerative disease with no cure currently available. Using cell-based functional assays, I will define the region(s) of progranulin which are bioactive, determine the effects of progranulin's structure on its function, and test the potential utility of a novel therapeutic approach for treating progranuln-deficient frontotemporal dementia. Completion of these studies will significantly advance our understanding of progranulin's activity and biochemical nature, and this knowledge will provide a biochemical framework for future studies aimed at understanding progranulin's precise function and how progranulin mutations cause frontotemporal dementia.

Agency
National Institute of Health (NIH)
Type
Career Transition Award (K99)
Project #
1K99AG047339-01A1
Application #
8791566
Study Section
Neuroscience of Aging Review Committee (NIA)
Program Officer
Petanceska, Suzana
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard University
Department
Genetics
Type
Schools of Public Health
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115