Frontotemporal dementia (FTD) is a progressive, fatal neurodegenerative disorder in which patients suffer personality changes, social withdrawal, and disinhibition. There is currently no treatment for this disease. Loss-of-function mutations in progranulin (GRN) that cause progranulin deficiency are a major genetic cause of FTD (5-10% of all cases). Grn+/- and Grn-/- mice are an animal model of progranulin deficiency, and may model some of the behavioral and neuronal dysfunction seen in FTD. Both Grn+/- and Grn-/- mice develop abnormal social behavior, conditioned fear deficits, and amygdala dysfunction around 6 months of age. Grn-/- mice also develop lipofuscinosis that may model neuronal ceroid lipofuscinosis, which occurs in patients homozygous for loss-of-function GRN mutations. The mechanism by which progranulin deficiency causes neuronal dysfunction is unknown, and is a key gap in our understanding of FTD. Grn+/- mice may be a useful model to address this question. In preliminary studies, we observed elevated phosphorylation of ribosomal protein S6 (Ser235/236) and Akt (Ser473) in the amygdala of Grn+/- mice. These data suggest increased signaling in the mTOR pathway, which causes abnormal social behavior in other mouse models. The goal of this proposal is to investigate the hypothesis that progranulin deficiency causes abnormal social behavior, conditioned fear, and amygdala dysfunction through elevated mTOR signaling. We will investigate this hypothesis using Grn+/+ and Grn+/- mice.
In aim 1 we will determine if increased mTOR signaling causes abnormal behavior and amygdala dysfunction in progranulin-deficient mice. First, we will measure phosphorylated and total levels of mTOR pathway signaling molecules (p-Akt, p-mTOR, p-S6 kinase, and p-S6) in FTD-associated brain regions (amygdala and prefrontal cortex) and a region not expected to be affected (cerebellum) in Grn+/+ and Grn+/- mice at ages before (3 months), during (5 and 7 months) and after (9 months) the transition to abnormal behavior. We will then determine if inhibiting mTOR signaling will prevent or reverse the phenotype of Grn+/- mice. Mice will be fed either a control or a rapamycin-supplemented diet for four weeks before (age 5-6 months) or after (age 9-12 months) the emergence of abnormal behavior. Immediately after this four week period, the mice will be tested for abnormal behavior and amygdala dysfunction. Amygdala function will be tested by measuring c-Fos expression after exposure to a novel, social environment. Inhibition of mTOR signaling will be confirmed by western blotting of cortex and amygdala samples.
In aim 2 we will investigate whether increasing progranulin levels with an AAV-Grn vector will normalize behavior, amygdala function, and mTOR signaling in Grn+/- mice. We will infuse AAV-Grn or AAV- Gfp into the prefrontal cortex and amygdala of Grn+/+ and Grn+/- before (age 5-6 months) or after (age 9-12 months) the emergence of abnormal behavior. Behavior, amygdala function, and mTOR signaling will be tested four weeks after AAV injection, using the assays described in aim one.
Frontotemporal dementia (FTD) is a devastating neurodegenerative disease in which patients experience personality changes, social withdrawal, and early death. This project investigates the molecular mechanisms by which progranulin deficiency causes FTD. Successful completion of this project could facilitate development of new therapies for FTD, a disease for which there are currently no effective treatments.
|Arrant, Andrew E; Filiano, Anthony J; Patel, Aashka R et al. (2018) Reduction of microglial progranulin does not exacerbate pathology or behavioral deficits in neuronal progranulin-insufficient mice. Neurobiol Dis 124:152-162|
|Arrant, Andrew E; Onyilo, Vincent C; Unger, Daniel E et al. (2018) Progranulin Gene Therapy Improves Lysosomal Dysfunction and Microglial Pathology Associated with Frontotemporal Dementia and Neuronal Ceroid Lipofuscinosis. J Neurosci 38:2341-2358|
|Arrant, Andrew E; Filiano, Anthony J; Unger, Daniel E et al. (2017) Restoring neuronal progranulin reverses deficits in a mouse model of frontotemporal dementia. Brain 140:1447-1465|
|Arrant, A E; Filiano, A J; Warmus, B A et al. (2016) Progranulin haploinsufficiency causes biphasic social dominance abnormalities in the tube test. Genes Brain Behav 15:588-603|