IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-33500-9.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-33500-9
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-33500-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    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.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Pasqualina Colella & Ruhi Sayana & Maria Valentina Suarez-Nieto & Jolanda Sarno & Kwamina Nyame & Jian Xiong & Luisa Natalia Pimentel Vera & Jessica Arozqueta Basurto & Marco Corbo & Anay Limaye & Kar, 2024. "CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice," Nature Communications, Nature, vol. 15(1), pages 1-26, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Daniel J. Lodge & Hannah B. Elam & Angela M. Boley & Jennifer J. Donegan, 2023. "Discrete hippocampal projections are differentially regulated by parvalbumin and somatostatin interneurons," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Hideyuki Takahashi & Sanaea Bhagwagar & Sarah H. Nies & Hongping Ye & Xianlin Han & Marius T. Chiasseu & Guilin Wang & Ian R. Mackenzie & Stephen M. Strittmatter, 2024. "Reduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    3. Yachao He & Ibrahim Kaya & Reza Shariatgorji & Johan Lundkvist & Lars U. Wahlberg & Anna Nilsson & Dejan Mamula & Jan Kehr & Justyna Zareba-Paslawska & Henrik Biverstål & Karima Chergui & Xiaoqun Zhan, 2023. "Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    4. Pasqualina Colella & Ruhi Sayana & Maria Valentina Suarez-Nieto & Jolanda Sarno & Kwamina Nyame & Jian Xiong & Luisa Natalia Pimentel Vera & Jessica Arozqueta Basurto & Marco Corbo & Anay Limaye & Kar, 2024. "CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice," Nature Communications, Nature, vol. 15(1), pages 1-26, December.
    5. Rachel Tesla & Charlotte Guhl & Gordon C. Werthmann & Danielle Dixon & Basar Cenik & Yesu Addepalli & Jue Liang & Daniel M. Fass & Zachary Rosenthal & Stephen J. Haggarty & Noelle S. Williams & Bruce , 2024. "Benzoxazole-derivatives enhance progranulin expression and reverse the aberrant lysosomal proteome caused by GRN haploinsufficiency," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33500-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.