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

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.

Grant Number: 5R01NS128031-04
NIH Institute/Center: NIH
Principal Investigator: Andrew Arrant