RF1AG079318

Resolving the Function of Progranulin in Lysosomal Lipid Metabolism and the Etiology of Alzheimer's Disease and Frontotemporal Dementia

Frontotemporal degeneration (FTD) and Alzheimer's disease (AD) are two of the most common causes of dementia. They share overlapping pathologies and are significant health burdens, yet they remain incurable. This proposal aims to elucidate how the loss of progranulin (PGRN) leads to lysosome dysfunction and lipid dysregulation associated with FTD and AD.

PGRN is a secreted protein composed of 7.5 tandem domains called granulins. Genetic variants and loss-of-function mutations in the progranulin gene (GRN) reduce PGRN levels and increase the risk of AD and cause FTD, respectively. Despite its importance in brain health, the exact function of PGRN and granulins remains unknown.

Research from our lab and others has shown that PGRN is cleaved into 6 kDa granulin proteins in the lysosome. It is believed that PGRN serves as a precursor to lysosomal granulins, which mediate lysosome homeostasis. Loss of granulins leads to impaired lysosome function. However, the specific function of granulins in the lysosome is still unclear.

Based on our published work and new data, we propose that the loss of granulins impairs lysosomal lipid metabolism, which is the primary defect that ultimately leads to neurodegeneration. Integrated analysis of the GRN-/- mouse metabolome and lipidome has revealed early accumulation of glycosphingolipids, phospholipids, and monoglycerides. Systems biology analysis of this data has identified dysregulated lysosomal lipid flux as a primary defect in GRN-/- tissue. Furthermore, we have identified decreased activity of a novel lysosomal hydrolase as a key factor.

Based on these findings, we hypothesize that granulins bind and modulate the activity of lysosomal lipid hydrolases to prevent lipid accumulation and neurodegeneration. In this project, we will: 1) determine the global and lysosome-specific molecular defects caused by PGRN deficiency in human induced pluripotent stem cell (iPSC)-derived neurons and microglia, 2) test the hypothesis that granulins modulate the activity of lipid hydrolases in the lysosomal lumen, and 3) define how PGRN deficiency alters the metabolome and lipidome in mice and humans.

Completion of these studies will provide novel systems-level insight into the function of granulins in the lysosome. The reagents and data generated from this research will be widely shared to advance our field's understanding of PGRN function. Our team is ideally suited to complete the proposed studies, which critically evaluate the novel hypothesis that granulins facilitate the metabolism of distinct lipids in the lysosome through the activation of novel lipid hydrolases to prevent lipid accumulation and neurodegeneration. By doing so, we aim to uncover why decreased levels of PGRN and granulins cause FTD and AD, and reveal new targets to treat diseases caused by PGRN deficiency.

Emory University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Atlanta, Georgia 30322 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the End Date has been extended from 08/31/25 to 08/31/27 and the total obligations have increased 65% from $2,098,104 to $3,471,933.