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Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis

Author

Listed:
  • Sebastian Boland

    (Harvard T. H. Chan School of Public Health
    Harvard Medical School)

  • Sharan Swarup

    (Harvard Medical School
    Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network)

  • Yohannes A. Ambaw

    (Harvard T. H. Chan School of Public Health
    Harvard Medical School
    Harvard T. H. Chan School of Public Health)

  • Pedro C. Malia

    (Harvard T. H. Chan School of Public Health
    Harvard Medical School)

  • Ruth C. Richards

    (Harvard T. H. Chan School of Public Health
    Harvard Medical School)

  • Alexander W. Fischer

    (Harvard T. H. Chan School of Public Health
    Harvard Medical School)

  • Shubham Singh

    (Harvard T. H. Chan School of Public Health
    Harvard Medical School)

  • Geetika Aggarwal

    (Saint Louis University School of Medicine)

  • Salvatore Spina

    (University of California, San Francisco)

  • Alissa L. Nana

    (University of California, San Francisco)

  • Lea T. Grinberg

    (University of California, San Francisco
    University of California at San Francisco)

  • William W. Seeley

    (University of California, San Francisco
    University of California at San Francisco)

  • Michal A. Surma

    (Lipotype GmbH)

  • Christian Klose

    (Lipotype GmbH)

  • Joao A. Paulo

    (Harvard Medical School)

  • Andrew D. Nguyen

    (Saint Louis University School of Medicine)

  • J. Wade Harper

    (Harvard Medical School
    Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network)

  • Tobias C. Walther

    (Harvard T. H. Chan School of Public Health
    Harvard Medical School
    Harvard T. H. Chan School of Public Health
    Howard Hughes Medical Institute)

  • Robert V. Farese

    (Harvard T. H. Chan School of Public Health
    Harvard Medical School
    Harvard T. H. Chan School of Public Health
    Broad Institute of Harvard and MIT)

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.

Suggested Citation

  • 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 , 2022. "Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33500-9
    DOI: 10.1038/s41467-022-33500-9
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    References listed on IDEAS

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    1. Alexandra M. Nicholson & NiCole A. Finch & Marcio Almeida & Ralph B. Perkerson & Marka van Blitterswijk & Aleksandra Wojtas & Basar Cenik & Sergio Rotondo & Venette Inskeep & Laura Almasy & Thomas Dye, 2016. "Prosaposin is a regulator of progranulin levels and oligomerization," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
    2. Matt Baker & Ian R. Mackenzie & Stuart M. Pickering-Brown & Jennifer Gass & Rosa Rademakers & Caroline Lindholm & Julie Snowden & Jennifer Adamson & A. Dessa Sadovnick & Sara Rollinson & Ashley Cannon, 2006. "Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17," Nature, Nature, vol. 442(7105), pages 916-919, August.
    3. Marc Cruts & Ilse Gijselinck & Julie van der Zee & Sebastiaan Engelborghs & Hans Wils & Daniel Pirici & Rosa Rademakers & Rik Vandenberghe & Bart Dermaut & Jean-Jacques Martin & Cornelia van Duijn & K, 2006. "Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21," Nature, Nature, vol. 442(7105), pages 920-924, August.
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