PROJECT SUMMARY The objective of the proposed research project is to further understand how progranulin (GRN) and β- glucocerebrosidase (GCase) interact and the implications of these interactions in frontotemporal dementia (FTD) caused by progranulin mutations. Frontotemporal dementia is a leading cause of early-onset dementia, and loss- of-function progranulin mutations are one of three main genetic causes. Progranulin is a secreted and lysosome- resident glycoprotein, and deficiency causes lysosomal dysfunction in patients and in mice. Progranulin-boosting therapies have promise for treating FTD-GRN, but delivery is an issue and the safety profile is unclear. This underscores a critical need to continue to search for targeted therapeutics with known safety profiles. Thus, a targeted therapy that reduces progranulin deficiency-induced lysosomal dysfunction may have therapeutic benefits for preventing or delaying FTD-GRN. In order to understand the underlying lysosomal dysfunction caused by progranulin deficiency, our lab has characterized the activities of several lysosomal enzymes in the brains of FTD-GRN patients and progranulin- deficient mice. We found decreased activity of neuronal GCase, a lysosomal enzyme, whereas other lysosomal enzymes show increased activity. GCase is an interesting target because of its known involvement in neurodegenerative disease, as GCase mutations are the leading genetic risk factor for Parkinson disease and the monogenic cause of Gaucher disease, a lysosomal storage disease with neurodegenerative subtypes. GCase deficiency in FTD-GRN appears to be due to an impairment in glycosylation causing GCase aggregation. This proposal will determine if progranulin deficiency impairs GCase trafficking, resulting in decreased lysosomal localization. The overarching hypothesis is that impaired progranulin-mediated GCase trafficking contributes to lysosomal dysfunction and other deficits caused by progranulin deficiency. This proposal will test the following two aims: (1) Determine how progranulin regulates trafficking of GCase and (2) Determine if GCase deficits contribute to lysosomal dysfunction and other deficits caused by progranulin deficiency. More work is needed to understand the specifics and effects of the progranulin-GCase interaction. I will first determine the domain of progranulin responsible for GCase interaction and will then test the effects of this interaction on GCase stability and lysosomal trafficking. I will then determine if increasing GCase is sufficient to reduce lysosomal dysfunction and behavioral abnormalities in progranulin-deficient mice. This proposal will facilitate my scientific and professional development by helping me: 1) improve competency in rigorous experimental design and hypothesis testing, 2) refine known experimental techniques and develop skills for translational research, and 3) gain experience presenting data to both scientific and lay audiences.