Determining the therapeutic potential and mechanism of granulins to treat Batten disease and frontotemporal dementia
openNINDS - National Institute of Neurological Disorders and Stroke
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.
Up to $617K
health research