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Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis

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Boland, Sebastian, Swarup, Sharan, Ambaw, Yohannes A., Malia, Pedro C., Richards, Ruth C., Fischer, Alexander W., Singh, Shubham, Aggarwal, Geetika +11 more·2022·Nature Communications
DOI 10.1038/s41467-022-33500-9PMC PMC9546883

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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.

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Crossref · 10.1038/s41467-022-33500-9

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  • Expression of complex gangliosides GD1a and GT1 was reduced in E3S/S/P301S hippocampi.

    “In contrast, expression of complex gangliosides GD1a and GT1 found to be increased in progranulin deficient model of frontotemporal dementia (FTD)38, were reduced in E3S/S/P301S hippocampi (Fig. 3H).”

    From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [38]

    The Results section reports increased GD1 species in progranulin-deficient brains, supporting that part of the cited comparison. It reports lower GT1 abundance in human GRN FTD-TDP subjects, not an increase. The reduction in E3S/S/P301S hippocampi is the citing paper’s own result, not a finding attributed to this source. Page numbers were not provided in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • These gangliosides are known to form toxic aggregates commonly associated with neurodegenerative diseases including FTD and Gaucher's disease.

    “These gangliosides are known to form toxic aggregates commonly associated with neurodegenerative diseases including FTD38 and Gaucher’s disease63.”

    From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [38]

    The Results section reports increased ganglioside levels in the frontal lobes of patients with GRN-associated FTD. It does not say gangliosides form toxic aggregates; the Discussion refers instead to possible downstream aggregation of proteins. Gaucher’s disease is attached to a different citation in the citing sentence, so it is not assessed here. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The reduction in gangliosides, such as GD1a and GQ1b, suggests improved lysosomal function.

    “Conversely, the reduction in gangliosides, such as GD1a and GQ1b, suggests improved lysosomal function38, which could mitigate tau-induced toxicity.”

    From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [38]

    The Discussion (page not provided) links impaired lysosomal ganglioside catabolism to ganglioside accumulation, and the Results report that restoring BMP normalized elevated GM2 levels. This supports the general interpretation that reduced ganglioside accumulation may reflect better lysosomal degradation. The paper does not establish that reductions in GD1a or GQ1b indicate improved lysosomal function; it reports unchanged GD1 levels in PGRN-knockout HeLa cells. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • These gangliosides are known to form toxic aggregates commonly associated with neurodegenerative diseases such as FTD and Gaucher's disease.

    “These gangliosides are known to form toxic aggregates commonly associated with neurodegenerative diseases, such as frontotemporal dementia (FTD)38 and Gaucher’s disease58.”

    From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [38]

    The Results section reports increased ganglioside levels in frontal lobes from patients with GRN-associated FTD, supporting the FTD association attributed to this citation. The paper does not say that gangliosides form toxic aggregates; its Discussion refers instead to possible protein aggregation following gangliosidosis. Gaucher’s disease has a separate citation in the citing sentence and is not assessed here. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Boland, S., Swarup, S., Ambaw, Y. A., Malia, P. C., Richards, R. C., Fischer, A. W., Singh, S., Aggarwal, G., Spina, S., Nana, A. L., Grinberg, L. T., Seeley, W. W., Surma, M. A., Klose, C., Paulo, J. A., Nguyen, A. D., Harper, J. W., Walther, T. C., & Farese, R. V.
Affiliations
  • Harvard University (US)
  • Saint Louis University (US)
  • University of California, San Francisco (US)
  • Lipotype (Germany) (DE)
  • Broad Institute (US)
Corresponding author
  • Harper, J. Wade
  • Walther, Tobias C.
  • Farese, Robert V.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-10-07
Volume
13
Issue
1
Pages
5924-5924
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-33500-9
PMC
PMC9546883
OpenAlex
W4303446525
Cited by
97
References
3
Citations by year
2026: 16 · 2025: 29 · 2024: 29 · 2023: 21 · 2022: 2
FWCI
13.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
The Bluefield Project. Grant # not applicable.
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
frontotemporal dementia, GRN gene, progranulin, haploinsufficiency, gangliosidosis, gangliosides, glycosphingolipids, bis(monoacylglycero)phosphate, lysosomal catabolism, neurodegeneration, neuroinflammation, sialic acid
MeSH terms
Progranulins, Granulins, Animals, Gangliosides, Gangliosidoses, Humans, Lysosomes, Phosphates, N-Acetylneuraminic Acid, Mice, Frontotemporal Dementia

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