Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis.

Autor: Boland S; Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA., Swarup S; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA., Ambaw YA; Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA.; Center on Causes and Prevention of Cardiovascular Disease, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA., Malia PC; Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA., Richards RC; Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA., Fischer AW; Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA., Singh S; Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA.; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA., Aggarwal G; Department of Internal Medicine, Division of Geriatric Medicine, and Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA., Spina S; Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, 94158, USA., Nana AL; Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, 94158, USA., Grinberg LT; Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, 94158, USA.; Department of Pathology, University of California at San Francisco, San Francisco, CA, USA., Seeley WW; Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, 94158, USA.; Department of Pathology, University of California at San Francisco, San Francisco, CA, USA., Surma MA; Lipotype GmbH, Dresden, Germany., Klose C; Lipotype GmbH, Dresden, Germany., Paulo JA; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA., Nguyen AD; Department of Internal Medicine, Division of Geriatric Medicine, and Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA., Harper JW; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA. wade_harper@hms.harvard.edu.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA. wade_harper@hms.harvard.edu., Walther TC; Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA. twalther@hsph.harvard.edu.; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA. twalther@hsph.harvard.edu.; Center on Causes and Prevention of Cardiovascular Disease, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA. twalther@hsph.harvard.edu.; Howard Hughes Medical Institute, Boston, MA, 02115, USA. twalther@hsph.harvard.edu.; Broad Institute of Harvard and MIT, Cambridge, MA, 02124, USA. twalther@hsph.harvard.edu., Farese RV Jr; Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA. robert@hsph.harvard.edu.; Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA. robert@hsph.harvard.edu.; Center on Causes and Prevention of Cardiovascular Disease, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA. robert@hsph.harvard.edu.; Broad Institute of Harvard and MIT, Cambridge, MA, 02124, USA. robert@hsph.harvard.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Oct 07; Vol. 13 (1), pp. 5924. Date of Electronic Publication: 2022 Oct 07.
DOI: 10.1038/s41467-022-33500-9
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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