Deficiency of the Frontotemporal Dementia Gene GRN Results in Gangliosidosis

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Oct 7

PMID 36207292

Authors

Sebastian Boland

Sharan Swarup

Yohannes A Ambaw

Pedro C Malia

Ruth C Richards

Alexander W Fischer

Shubham Singh

Geetika Aggarwal

Salvatore Spina

Alissa L Nana

Lea T Grinberg

William W Seeley

Michal A Surma

Christian Klose

Joao A Paulo

Andrew D Nguyen

J Wade Harper

Tobias C Walther

Robert V Farese Jr

Affiliations

Soon will be listed here.

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.

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