Progranulin and Lysosomal pH: Implications for the Proinflammatory Response in Neurodegenerative Diseases

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Progranulin (PGRN) deficiency and lysosomal dysfunction have been independently linked to Alzheimer's disease. Several lines of evidence suggest that there is a link between PGRN and lysosomal function. PGRN is a pleiotropic signaling molecule whose activity depends upon differential proteolytic processing. The different PGRN subunits generated during processing can regulate inflammation, lysosomal function, and/or growth. Not only is the lysosome a site of PGRN processing, the resulting PGRN subunits promote the function of several lysosomal proteases. In addition, in models of PGRN insuffciency, increasing the levels of PGRN restores lysosomal function and reduces inflammation. As microglial inflammation is key to the development of neurodegenerative diseases, this work investigates the link between lysosomal function, PGRN, and inflammation utilizing two cell lines, each for a distinct set of experiments. The SW13 human adrenal carcinoma cell line that exists in two epigenetically distinct subtypes was used to focus on differences in lysosomal pH and PGRN processing. The HMC3 human microglial cell line was used to measure microglial activation and cytokine production. We hypothesize that PGRN, when appropriately processed, will restore lysosomal function to reduce pro-inflammatory cytokine production. Results suggest that differential processing of PGRN is correlated to both differences in rate of growth, inflammatory cytokine production, and lysosomal pH as PGRN expression and processing varies when cells are stimulated which may be related to observed changes in lysosomal pH and proteases. Ongoing experiments address the possibility that decreasing lysosomal pH may shift the processing of PGRN, influencing the biological activities associated with this versatile signaling molecule. As mutations in the PGRN gene are implicated in both dysfunctional lysosomal pH and a variety of neurodegenerative diseases, these results may provide a novel approach to regulate proper intracellular functions to slow or prevent the development of disease. Midwestern University Biomedical Sciences Program Funds awarded to AZY and PB; Kenneth A. Suarez Research Fellowship Funding awarded to PB; Arizona Alzheimer's Consortium Pilot Grant Funding awarded to EEH and KJL; Midwestern Arizona Alzheimer’s Consortium (MAAC) Grant Funding awarded to EEH and KJL; Midwestern University Intramural Funding awarded to EEH and KJL. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.