Journal Article

Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis

Grinberg, Lea T., Farese, Robert V., Richards, Ruth C., Spina, Salvatore, Klose, Christian, Swarup, Sharan, Nana, Alissa L., Seeley, William W., Surma, Michal A., Harper, J. Wade, Fischer, Alexander W., Malia, Pedro C., Nguyen, Andrew D., Boland, Sebastian, Ambaw, Yohannes A., Aggarwal, Geetika, Singh, Shubham, Walther, Tobias C., Paulo, Joao A.

2022

Overview

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. Progranulin-deficieny results in gangliosidosis due to reduced lysosomal lipids (BMP) required for ganglioside degradation. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/19 / 631/378/1689 / 631/92/287/1186 / 82/16 / 82/58 / 96/106 / 96/34 / Accumulation / Animals / Catabolism / Dementia / Dementia disorders / Frontotemporal dementia / Frontotemporal Dementia - genetics / Frontotemporal Dementia - metabolism / Gangliosides / Gangliosides - metabolism / Gangliosidoses - metabolism / Gangliosidosis / Glycosphingolipids / Granulin / Granulins - metabolism / Haploinsufficiency / Humanities and Social Sciences / Humans / Inflammation / Lipid metabolism / Lipids / Lysosomal enzymes / Lysosomes / Lysosomes - metabolism / Mice / multidisciplinary / Mutation / N-Acetylneuraminic Acid - metabolism / Neurodegeneration / Neurodegenerative diseases / Phosphates / Phosphates - metabolism / Polypeptides / Progranulins - genetics / Progranulins - metabolism / Science / Science (multidisciplinary)