Tissue-specific immune and MAPK signatures in models of reduced Progranulin and Western diet

TL;DR

Reduced Progranulin and a western diet affect immune and metabolic responses in mice, with implications for frontotemporal dementia.

Contribution

This study reveals tissue-specific immune and MAPK signaling disruptions in mice with reduced Progranulin under a western diet.

Findings

Full Grn loss increases antigen presentation and immune infiltration in the brain after a western diet.

Heterozygous Grn disruption affects peripheral immune responses and brain MAPK signaling.

Western diet exacerbates cellular stress in genetically predisposed mice.

Abstract

Neurodegenerative disorders such as frontotemporal dementia (FTD) have strong hereditary links, yet these genes do not have full penetrance and environmental influences determine the lifetime risk of disease development. Better understanding of the environmental risk factors that determine age of onset, progression, and severity is needed. How these risk factors interact with genetic predisposition for these disorders will allow clinicians to provide better lifestyle recommendations for people with a familial history and deliver more personalized medicine. Here we examine the dose-dependent effects of the gene encoding progranulin (Grn), one of the most common mutations associated with familial FTD. We utilize both homozygous loss and heterozygous knockdown of Grn with the objective of assessing how a western diet consisting of high-fat and high-carbohydrate intake modulates the inflammatory and metabolic hallmarks in middle-aged mice. We found that while full Grn loss leads to heighted antigen presentation machinery and immune cell infiltration in the brain after obesogenic diet, a heterozygous gene primarily affects the periphery. Yet, further examination by RNA sequencing reveals that heterozygous mice have a disruption of MAPK signaling in the brain highlighting early disruption in the neuronal landscape. Our findings are consistent with reports that in individuals with genetic predisposition for FTD due to a GRN mutation, a western-style diet exacerbates the cellular stress in the peripheral immune system and affects the function of the prefrontal cortex. These data further support the use of heterozygous Grn knockout mice as a model for prodromal FTD in addition to the more common Grn full knockout which may not as accurately reflect disease onset biology.

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