Dataset Information

Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis.

ABSTRACT: Haploinsufficiency of GRN causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), which is cleaved to lysosomal granulin polypeptides. The function of lysosomal granulins and why their absence causes neurodegeneration are unclear. Here we discover that PGRN-deficient human cells and murine brains, as well as human frontal lobes from GRN-mutation FTD patients have increased levels of gangliosides, glycosphingolipids that contain sialic acid. In these cells and tissues, levels of lysosomal enzymes that catabolize gangliosides were normal, but levels of bis(monoacylglycero)phosphates (BMP), lipids required for ganglioside catabolism, were reduced with PGRN deficiency. Our findings indicate that granulins are required to maintain BMP levels to support ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD due to PGRN deficiency and other neurodegenerative diseases.

SUBMITTER: Boland S

PROVIDER: S-EPMC9546883 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis.

Boland Sebastian S Swarup Sharan S Ambaw Yohannes A YA Malia Pedro C PC Richards Ruth C RC Fischer Alexander W AW Singh Shubham S Aggarwal Geetika G Spina Salvatore S Nana Alissa L AL Grinberg Lea T LT Seeley William W WW Surma Michal A MA Klose Christian C Paulo Joao A JA Nguyen Andrew D AD Harper J Wade JW Walther Tobias C TC Farese Robert V RV

Nature communications 20221007 1

Haploinsufficiency of GRN causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), which is cleaved to lysosomal granulin polypeptides. The function of lysosomal granulins and why their absence causes neurodegeneration are unclear. Here we discover that PGRN-deficient human cells and murine brains, as well as human frontal lobes from GRN-mutation FTD patients have increased levels of gangliosides, glycosphingolipids that contain sialic acid. In these cells and tissues, le ...[more]

PMID: 36207292

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Project description:Heterozygous mutations in the GRN gene and hexanucleotide repeat expansions in C9orf72 are the two most common genetic causes of Frontotemporal Dementia (FTD) with TDP-43 protein inclusions. The triggers for neurodegeneration in FTD with GRN (FTD-GRN) or C9orf72 (FTD-C9orf72) gene abnormalities are unknown, although evidence from mouse and cell culture models suggests that GRN mutations disrupt lysosomal lipid catabolism. To determine how brain lipid metabolism is affected in familial FTD with TDP-43 inclusions, and how this is related to myelin and lysosomal markers, we undertook comprehensive lipidomic analysis, enzyme activity assays, and western blotting on grey and white matter samples from the heavily-affected frontal lobe and less-affected parietal lobe of FTD-GRN cases, FTD-C9orf72 cases, and age-matched neurologically-normal controls. Substantial loss of myelin-enriched sphingolipids (sulfatide, galactosylceramide, sphingomyelin) and myelin proteins was observed in frontal white matter of FTD-GRN cases. A less-pronounced, yet statistically significant, loss of sphingolipids was also observed in FTD-C9orf72. FTD-GRN was distinguished from FTD-C9orf72 and control cases by increased acylcarnitines in frontal grey matter and marked accumulation of cholesterol esters in both frontal and parietal white matter, indicative of myelin break-down. Both FTD-GRN and FTD-C9orf72 cases showed significantly increased lysosomal and phagocytic protein markers, however galactocerebrosidase activity, required for lysosomal catabolism of galactosylceramide and sulfatide, was selectively increased in FTD-GRN. We conclude that both C9orf72 and GRN mutations are associated with disrupted lysosomal homeostasis and white matter lipid loss, but GRN mutations cause a more pronounced disruption to myelin lipid metabolism. Our findings support the hypothesis that hyperactive myelin lipid catabolism is a driver of gliosis and neurodegeneration in FTD-GRN. Since FTD-GRN is associated with white matter hyperintensities by MRI, our data provides important biochemical evidence supporting the use of MRI measures of white matter integrity in the diagnosis and management of FTD.

Project description:TAR DNA-binding protein 43 (TDP-43) inclusions are pathological hallmarks of patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Loss of TDP-43 in zebrafish engenders a severe muscle and vascular phenotype with a concomitant elevation of filamin C (FLNC) levels, an observation confirmed in the frontal cortex of FTLD-TDP patients. Here, we aimed to further assess the contribution of FLNC to frontotemporal dementia (FTD) etiology. We conducted a mutational screening of FLNC in a cohort of 529 unrelated Belgian FTD and FTD-ALS patients, and a control cohort of 920 unrelated and age-matched individuals. Additionally we performed an in-depth characterization of FLNC expression levels in FTD patients and a murine FTD model.In total 68 missense variants were identified of which 19 (MAF < 1%) were patient-only. Gene burden analysis demonstrated a significant association between the presence of rare variants in FLNC and disease (P = 0.0349, RR = 1.46 [95% CI 1.03-2.07]). Furthermore, elevated FLNC expression levels, observed previously in FTLD-TDP patients, were mainly attributable to FTD patients with the progranulin (GRN) p.0(IVS1 + 5G > C) loss-of-function mutation. Increased FLNC levels were, to a lesser extent, also identified in a FLNC p.V831I variant carrier and in FTD patients with the p.R159H mutation in valosin-containing protein (VCP). The GRN-associated increase of FLNC was confirmed in the frontal cortex of aged Grn knockout mice starting at 16-18 months of age. Combined quantitative proteomic and bioinformatic analyses of the frontal cortex of FTD patients possessing elevated FLNC levels, identified multiple altered protein factors involved in accelerated aging, neurodegeneration and synaptogenesis.Our findings further support the involvement of aberrant FLNC expression levels in FTD pathogenesis. Identification of increased FLNC levels in aged Grn mice and impaired pathways related to aging and neurodegeneration, implies a potential role for FLNC in mediating or accelerating the aging process.

Dataset Information

Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis.

Publications

Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis.

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