RT Journal Article SR Electronic T1 Progranulin deficiency results in reduced bis(monoacylglycero)phosphate (BMP) levels and gangliosidosis JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.09.30.461806 DO 10.1101/2021.09.30.461806 A1 Sebastian Boland A1 Sharan Swarup A1 Yohannes A. Ambaw A1 Ruth C. Richards A1 Alexander W. Fischer A1 Shubham Singh A1 Geetika Aggarwal A1 Salvatore Spina A1 Alissa L. Nana A1 Lea T. Grinberg A1 William W. Seeley A1 Michal A. Surma A1 Christian Klose A1 Joao A. Paulo A1 Andrew D. Nguyen A1 J. Wade Harper A1 Tobias C. Walther A1 Robert V. Farese, Jr. YR 2021 UL http://biorxiv.org/content/early/2021/09/30/2021.09.30.461806.abstract AB Homozygous mutations of granulin precursor (GRN) lead to neuronal ceroid lipofuscinosis1, a severe neurodevelopmental disease, in humans and neuroinflammation in mice2. Haploinsufficiency of GRN almost invariably causes frontotemporal dementia (FTD)3,4. The GRN locus produces progranulin (PGRN), a lysosomal precursor protein that is cleaved to granulin peptides5,6. 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 patients with GRN mutation-related 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 catabolism7, were markedly reduced in PGRN-deficient cells and patient 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.Competing Interest StatementThe authors have declared no competing interest.