Progranulin deficiency results in reduced bis(monoacylglycero)phosphate (BMP) levels and gangliosidosis

Abstract

Homozygous mutations of granulin precursor (GRN) lead to neuronal ceroid lipofuscinosis, a severe neurodevelopmental disease, in humans and neuroinflammation in mice. Haploinsufficiency of GRN almost invariably causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), a lysosomal precursor protein that is cleaved to granulin peptides. Despite intensive investigation, the function of granulins and the reason why their absence causes neurodegeneration remain unclear. Here, we investigated PGRN function in lipid degradation, a major function of lysosomes. We show that PGRN knockout human cells, PGRN-deficient murine brain, and frontal lobes of human brains from subjects with PGRN deficient FTD have increased levels of gangliosides, highly abundant sialic acid containing glycosphingolipids (GSL) that are degraded in lysosomes. Probing how PGRN deficiency causes these changes, we found normal levels and activities of enzymes that catabolize gangliosides. However, levels of bis(monoacylglycero)phosphate (BMP), a lysosomal lipid required for ganglioside catabolism, were markedly reduced in PGRN deficient cells and brain tissues. These data indicate that granulins are required to maintain BMP levels, which regulate ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. This aberrant accumulation of gangliosides may contribute to neuroinflammation and neurodegeneration susceptibility.

Upstream lipid and metabolic systems are potential causes of Alzheimer's disease, Parkinson's disease and dementias

“…Homozygous mutations in granulin precursor (GRN) cause neuronal ceroid lipofuscinosis (NCL) in childhood while FTD can be caused by heterozygous GRN mutations and presents in adulthood. GRN FTD patients accumulate lipids in the brain and the cerebrospinal fluid (CSF) and serum contains inflammatory biomarkers [59][60][61][62][63][64]. Similar results linking lipid accumulation to inflammation have been observed in experimental models (Fig.…”