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Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations

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Marian, Oana C., Teo, Jonathan D., Lee, Jun Yup, Song, Huitong, Kwok, John B., Landin-Romero, Ramon, Halliday, Glenda, Don, Anthony S.·2023·Acta Neuropathologica Communications
DOI 10.1186/s40478-023-01544-7PMC PMC10041703
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Abstract

Heterozygous mutations in the GRN gene and hexanucleotide repeat expansions in C9orf72 are the two most common genetic causes of Frontotemporal Dementia (FTD) with TDP-43 protein inclusions. The triggers for neurodegeneration in FTD with GRN (FTD-GRN) or C9orf72 (FTD-C9orf72) gene abnormalities are unknown, although evidence from mouse and cell culture models suggests that GRN mutations disrupt lysosomal lipid catabolism. To determine how brain lipid metabolism is affected in familial FTD with TDP-43 inclusions, and how this is related to myelin and lysosomal markers, we undertook comprehensive lipidomic analysis, enzyme activity assays, and western blotting on grey and white matter samples from the heavily-affected frontal lobe and less-affected parietal lobe of FTD-GRN cases, FTD-C9orf72 cases, and age-matched neurologically-normal controls. Substantial loss of myelin-enriched sphingolipids (sulfatide, galactosylceramide, sphingomyelin) and myelin proteins was observed in frontal white matter of FTD-GRN cases. A less-pronounced, yet statistically significant, loss of sphingolipids was also observed in FTD-C9orf7 2. FTD-GRN was distinguished from FTD-C9orf72 and control cases by increased acylcarnitines in frontal grey matter and marked accumulation of cholesterol esters in both frontal and parietal white matter, indicative of myelin break-down. Both FTD-GRN and FTD-C9orf72 cases showed significantly increased lysosomal and phagocytic protein markers, however galactocerebrosidase activity, required for lysosomal catabolism of galactosylceramide and sulfatide, was selectively increased in FTD-GRN. We conclude that both C9orf72 and GRN mutations are associated with disrupted lysosomal homeostasis and white matter lipid loss, but GRN mutations cause a more pronounced disruption to myelin lipid metabolism. Our findings support the hypothesis that hyperactive myelin lipid catabolism is a driver of gliosis and neurodegeneration in FTD-GRN. Since FTD-GRN is associated with white matter hyperintensities by MRI, our data provides important biochemical evidence supporting the use of MRI measures of white matter integrity in the diagnosis and management of FTD.

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  • Increased levels of sphingosines indicate elevated myelin metabolism in ALDH5A1 KO mice.

    “However, the increased levels of sphingosines also indicate elevated myelin metabolism, as sphingosines provide the backbone of Hex1Cer and sulfatides, and thus accumulate when sphingolipids are broken down (Marian et al., 2023).”

    From Deficient brain <scp>GABA</scp> metabolism leads to widespread impairments of astrocyte and oligodendrocyte function (2024) · cites this paper as Marian et al., 2023

    The Discussion (page unavailable) calls sphingosine a sphingolipid catabolic intermediate and says its increase could reflect accelerated myelin breakdown. It also says accumulation could instead result from blocked lysosomal catabolism; the paper does not establish elevated myelin metabolism in ALDH5A1 knockout mice. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Marian, O. C., Teo, J. D., Lee, J. Y., Song, H., Kwok, J. B., Landin-Romero, R., Halliday, G., & Don, A. S.
Affiliations
The University of Sydney (AU)
Corresponding author
Don, Anthony S.
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2023-03-27
Volume
11
Issue
1
Pages
52-52
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-023-01544-7
PMC
PMC10041703
OpenAlex
W4360978909
Cited by
50
References
9
Citations by year
2026: 10 · 2025: 20 · 2024: 18 · 2023: 2
FWCI
8.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Health and Medical Research Council (APP1163249, APP2002660, 1176607)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
frontotemporal dementia, GRN mutations, C9orf72 repeat expansion, sphingolipids, galactocerebrosidase, acylcarnitines, cholesterol esters, white matter integrity, TDP-43 inclusions, neurodegeneration, gliosis
MeSH terms
C9orf72 Protein, Progranulins, Animals, DNA-Binding Proteins, Galactosylceramides, Humans, Mutation, Myelin Sheath, Sulfoglycosphingolipids, Pick Disease of the Brain, Lipid Metabolism, Mice, Frontotemporal Dementia

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