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Cited by 31Lysosomal Storage Disorders ResearchParkinson's Disease Mechanisms and TreatmentsMetabolism and Genetic Disorders

Elevation of gangliosides in four brain regions from Parkinson’s disease patients with a GBA mutation

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Blumenreich, Shani, Nehushtan, Tamar, Barav, Or B., Saville, Jennifer T., Dingjan, Tamir, Hardy, John, Fuller, Maria, Futerman, Anthony H.·2022·npj Parkinson's Disease
DOI 10.1038/s41531-022-00363-2PMC PMC9357011
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Abstract

A number of genetic risk factors have been identified over the past decade for Parkinson’s Disease (PD), with variants in GBA prominent among them. GBA encodes the lysosomal enzyme that degrades the glycosphingolipid, glucosylceramide (GlcCer), with the activity of this enzyme defective in Gaucher disease. Based on the ill-defined relationship between glycosphingolipid metabolism and PD, we now analyze levels of various lipids by liquid chromatography/electrospray ionization-tandem mass spectrometry in four brain regions from age- and sex-matched patient samples, including idiopathic PD, PD patients with a GBA mutation and compare both to control brains (n = 21 for each group) obtained from individuals who died from a cause unrelated to PD. Of all the glycerolipids, sterols, and (glyco)sphingolipids (251 lipids in total), the only lipid class which showed significant differences were the gangliosides (sialic acid-containing complex glycosphingolipids), which were elevated in 3 of the 4 PD-GBA brain regions. There was no clear correlation between levels of individual gangliosides and the genetic variant in Gaucher disease [9 samples of severe (neuronopathic), 4 samples of mild (non-neuronopathic) GBA variants, and 8 samples with low pathogenicity variants which have a higher risk for development of PD]. Most brain regions, i.e. occipital cortex, cingulate gyrus, and striatum, did not show a statistically significant elevation of GlcCer in PD-GBA. Only one region, the middle temporal gyrus, showed a small, but significant elevation in GlcCer concentration in PD-GBA. We conclude that changes in ganglioside, but not in GlcCer levels, may contribute to the association between PD and GBA mutations.

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  • 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 [63]

    The Discussion (page not provided) says exosomes containing gangliosides may accelerate α-synuclein aggregation and reports elevated gangliosides in Parkinson’s patients with a GBA mutation. It does not say that gangliosides themselves form toxic aggregates, or establish that such aggregates are associated with Gaucher’s disease. (LLM, conf=0.86)

    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 [58]

    The Discussion says exosomes containing gangliosides may accelerate α-synuclein aggregation in Parkinson’s disease with a GBA mutation. It does not say that gangliosides themselves form toxic aggregates in Gaucher’s disease; the Introduction identifies different lipids, glucosylceramide and glucosylsphingosine, as accumulating in that disease. The FTD example has a separate citation in the citing sentence. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 47

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Cited by

Sorted by citations

Authors
Blumenreich, S., Nehushtan, T., Barav, O. B., Saville, J. T., Dingjan, T., Hardy, J., Fuller, M., & Futerman, A. H.
Affiliations
  • Weizmann Institute of Science (IL)
  • South Australia Pathology (AU)
  • University College London (GB)
Corresponding author
Futerman, Anthony H.
ORCID
Venue
npj Parkinson's Disease
Publisher
Springer Science and Business Media LLC
Published
2022-08-06
Volume
8
Issue
1
Pages
99-99
ISSN
2373-8057 (ISSN-L)
DOI
10.1038/s41531-022-00363-2
PMC
PMC9357011
OpenAlex
W4290026893
Cited by
31
References
0
Citations by year
2026: 7 · 2025: 11 · 2024: 9 · 2023: 4
FWCI
3.72
Type
journal article
Language
en
Open access
Licence
Locations
  • npj Parkinson s Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Michael J. Fox Foundation for Parkinson's Research (16132)
  • Children's Gaucher Research Fund
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
Parkinson's disease, GBA mutations, gangliosides, glucosylceramide, glycosphingolipid metabolism, lysosomal storage disease, Gaucher disease, genetic risk factors, sialic acid, middle temporal gyrus, striatum, occipital cortex, cingulate gyrus

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