Wednesday, April 24, 2024
4/24/2024
Project Summary/Abstract Genetic studies indicate a link between low progranulin levels and neurodegenerative disease. Loss-of- function progranulin (GRN) mutations are one of the most common dominant genetic causes of frontotemporal dementia (FTD), accounting for around 5% of FTD cases. GRN polymorphisms are associated with increased risk for Alzheimer's disease (AD), FTD, and Parkinson's disease. Most pathogenic GRN mutations cause progranulin haploinsufficiency, and the best-known GRN polymorphism that increases risk of AD and FTD is associated with around 20% reduction of progranulin. Progranulin is secreted by multiple cell types throughout the body and is present in both blood and cerebrospinal fluid (CSF). Extracellular progranulin may interact with cell-surface signaling receptors to exert neurotrophic and anti-inflammatory effects. Extracellular progranulin is also taken up by cells and trafficked to lysosomes, where it enhances lysosomal enzyme activity. Progranulin haploinsufficiency is thought to drive FTD pathogenesis in GRN mutation carriers through loss of these beneficial effects. Progranulin-boosting therapies are under development to correct progranulin haploinsufficiency in GRN mutation carriers, either by increasing progranulin expression or reducing progranulin uptake. Both strategies should increase levels of extracellular progranulin, which could produce widespread correction of progranulin haploinsufficiency. However, very little is known about the regulation of extracellular progranulin in the brain. This is a major gap in the field that limits our ability to test progranulin- boosting therapies and investigate the physiologic functions of progranulin. Studies of progranulin in blood and CSF indicate differential regulation of extracellular progranulin levels in the periphery versus the central nervous system, highlighting the importance of studying extracellular progranulin in the brain. To address this need, we have adapted in vivo microdialysis to measure extracellular progranulin in the brain of mouse models. We propose to use this technique to investigate the mechanisms regulating brain extracellular progranulin levels. We hypothesize that brain extracellular progranulin levels are regulated by the balance between secretion and cellular uptake, and that these processes are dynamic, producing short-term fluctuations in extracellular progranulin levels. Progranulin is constitutively secreted, so in aim 1 we will test the hypothesis that progranulin expression is a major driver of secretion and thus extracellular progranulin levels. In aim 2 we will test the hypothesis that sortilin-mediated uptake is a major regulator of brain extracellular progranulin levels. We will conduct these experiments using a mouse-reactive analog of the sortilin-blocking antibody AL001, which is entering phase 2 clinical trials for FTD due to GRN mutations. In aim 3 we will test the hypothesis that neuronal activity increases brain extracellular progranulin levels. We anticipate that this work will lay the foundation for future studies of progranulin-boosting therapies and progranulin physiology.
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