Determining the therapeutic potential and mechanism of granulins to treat Batten disease and frontotemporal dementia

About This Grant

The long-term goal of this project is to understand how loss of progranulin (PGRN) causes neurodegeneration in frontotemporal degeneration (FTD) and neuronal ceroid lipofuscinosis (NCL), commonly called Batten’s disease. FTD and NCL are fatal and currently incurable. FTD and NCL have distinct clinical manifestations but share a causative genetic factor, the GRN gene, which encodes PGRN. PGRN is an 80 kDa secreted glycoprotein composed of 7.5 tandem proteins called granulins. Heterozygous GRN mutations decrease PGRN levels and are a common cause of FTD, the most frequent dementia before the age of 60. Importantly, complete loss of PGRN through homozygous GRN mutations causes the neurodegenerative lysosome storage disease NCL type 11 (CLN11). Thus, PGRN activity is important for lysosome function and brain health, yet the function of PGRN is unclear. Our lab discovered that PGRN localizes to the lysosome, is critical for lysosome homeostasis, and is rapidly processed in the lysosome into 7 individual stable 6-kDa granulins. New preliminary data show that treatment of Grn-/- mice with a single granulin, granulin-4, fully ameliorates neuropathology, lysosome dysfunction, and neuroinflammation. These data lead us to hypothesize that a novel receptor facilities lysosomal trafficking of PGRN and processing into granulins, which function to maintain bis(monoacylglycerol)phosphate (BMP) lipid levels that are necessary for lysosomal lipid catabolism to prevent neurodegeneration. Our team has the expertise and necessary tools to bring clarity to the function of granulins and test this novel hypothesis in three aims. In Aim 1, we will test the ability of each granulin to ameliorate lysosome dysfunction and neurodegeneration. In Aim 2, we will delineate the molecular pathways that traffic PGRN to the lysosome to produce granulins. In Aim 3, we will dissect the molecular mechanisms of granulin function in lysosome lipid metabolism. Completion of these studies will rigorously test the novel hypothesis that lysosomal granulins are the bioactive functional products of PGRN and potential pre- clinical therapeutics for FTD and NCL. Our results will provide clarity into the function of granulins in the lysosome, which has been a key question holding back the field. This project will help uncover how decreased PGRN and granulins cause lysosome dysfunction and neurodegeneration as well as elucidate new therapeutic targets for diseases caused by PGRN deficiency.