Mechanisms of Thalamocortical Dysfunction and Social Deficits in FTD due to GRN Mutations

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Project Summary/Abstract Loss of function progranulin (GRN) mutations, most of which cause haploinsufficiency, are a major genetic cause of frontotemporal dementia (FTD) with TDP-43 pathology (FTD-TDP). Progranulin-boosting therapies are a promising treatment strategy, but the optimal progranulin-boosting strategy remains unclear. Progranulin has pleiotropic effects and undergoes complex trafficking and processing, so the distribution of progranulin across cell types and cellular compartments may determine the efficacy and safety of progranulin-boosting therapies. Optimal progranulin-boosting therapies would retain progranulin’s neurotrophic and anti- inflammatory effects, with minimal risk of adverse effects such as promotion of tumor growth. Design of such therapies is impeded by our limited understanding of the pathogenesis of FTD due to GRN mutations (FTD- GRN). Our prior work highlights loss of progranulin’s neurotrophic effects as an important mechanism of FTD- GRN. Restoring neuronal progranulin corrects FTD-related social deficits in Grn+/– mice, and selective loss of neuronal progranulin reproduces these deficits. Social deficits in Grn+/– mice are associated with loss of dendritic arborization in the medial prefrontal cortex (mPFC), which with the mediodorsal thalamus (MDt) forms a critical circuit for social dominance behavior. MDt-mPFC connectivity is impaired in Grn+/– mice, modeling impaired thalamocortical connectivity in symptomatic FTD-GRN patients. Understanding the molecular mechanism of progranulin’s neurotrophic effects may thus be crucial for design of optimal progranulin-boosting therapies, but it is unclear if these effects are mediated by extracellular signaling or by enhancing lysosomal activity. We therefore developed a lysosome-targeted progranulin (L-PGRN) viral vector that delivers progranulin to lysosomes without secretion. L-PGRN reproduced several neurotrophic effects of progranulin in cultured neurons, so we hypothesize that progranulin acts in lysosomes to maintain the structure of FTD- related thalamocortical circuitry, and that selectively delivering progranulin to lysosomes will correct FTD- related behavioral deficits and pathology. We will test this hypothesis in primary cortical neurons and mouse models. In aim 1, we will determine if progranulin promotes dendritic arborization by enhancing cathepsin activity. In aim 2, we will determine if progranulin acts in lysosomes to maintain FTD-related thalamocortical circuitry. In aim 3, we will use a novel Grn+/–:TDP-43 transgenic mouse cross to determine if selectively boosting lysosomal progranulin will correct FTD-related social deficits and pathology. These aims have the potential to advance our understanding of FTD-GRN pathogenesis, and may provide insight into FTD-TDP and Alzheimer’s disease (AD), as a GRN polymorphism increases risk for FTD-TDP and AD. These studies may also inform design of progranulin-boosting therapies by revealing lysosomes as progranulin’s key site of action. Selectively delivering progranulin to lysosomes could effectively treat FTD with lower risk of adverse effects.