# Mitochondria and Lipid Defects in Hereditary Progranulin-Related Frontotemporal Dementia

## TL;DR

This study finds that a genetic mutation in GRN causes mitochondrial and lipid issues in cells from frontotemporal dementia patients, which could lead to new treatments.

## Contribution

The study identifies mitochondrial dysfunction and lipid metabolism disruption as novel features of GRN-related frontotemporal dementia.

## Key findings

- GRN-mutant fibroblasts show mitochondrial swelling and reduced respiration.
- Lipid metabolism is disrupted in GRN-mutant fibroblasts with lipid droplet accumulation.
- rhPGRN supplementation improves lysosomal and mitochondrial abnormalities in these cells.

## Abstract

What are the main findings?
FTD GRN-mutant fibroblasts replicate lysosome-related features observed in FTD patients.Fibroblasts from heterozygous GRN c.709-1G>A mutation carriers show altered mitochondrial function.Fibroblasts from heterozygous GRN c.709-1G>A mutation carriers exhibit disrupted lipid metabolism.

FTD GRN-mutant fibroblasts replicate lysosome-related features observed in FTD patients.

Fibroblasts from heterozygous GRN c.709-1G>A mutation carriers show altered mitochondrial function.

Fibroblasts from heterozygous GRN c.709-1G>A mutation carriers exhibit disrupted lipid metabolism.

What are the implications of the main findings?
FTD GRN-mutant fibroblasts provide a useful initial system to investigate lysosomal dysfunction and associated metabolic alterations relevant to FTD.These metabolic changes suggest that pathways related to mitochondrial and lipid homeostasis may represent areas of interest for future research.

FTD GRN-mutant fibroblasts provide a useful initial system to investigate lysosomal dysfunction and associated metabolic alterations relevant to FTD.

These metabolic changes suggest that pathways related to mitochondrial and lipid homeostasis may represent areas of interest for future research.

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting individuals under 65 years of age, characterized by significant behavioral and language disabilities. Despite extensive research efforts, effective treatments for FTD remain elusive. Familial cases of FTD have been linked to genetic mutations in several key genes, among these, mutations in granulin (GRN) account for 5–20% of cases, leading to haploinsufficiency of progranulin (PGRN), a multifunctional glycoprotein. This study investigates the cellular pathology associated with GRN insufficiency by using fibroblasts derived from FTD patients carrying the c.709-1G>A GRN mutation (FTD-GRN). These fibroblasts exhibited pathological hallmarks of FTD, including lysosomes, autophagosomes, and lipofuscin accumulation, mirroring observations in affected patient tissues. Notably, we report mitochondrial abnormalities, characterized by mitochondrial swelling which is associated with decreased mitochondrial respiration, and lipid droplet accumulation, reflecting altered lipid metabolism. Experimental supplementation with recombinant human progranulin (rhPGRN) was associated with recovery of lysosomal acidification and attenuation of mitochondrial and lipid abnormalities in vitro. This study reveals that GRN haploinsufficiency induces mitochondrial and lipid dysfunctions, suggesting that these pathways may contribute to FTD-GRN pathogenesis and could be of interest for therapeutic development.