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Cited by 14Amyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatmentsGenetic Neurodegenerative Diseases

Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice

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Rezaei, Ali, Kocsis-Jutka, Virág, Gunes, Zeynep I., Zeng, Qing, Kislinger, Georg, Bauernschmitt, Franz, Isilgan, Huseyin Berkcan, Parisi, Laura R. +22 more·2025·Nature Communications
DOI 10.1038/s41467-025-58634-4PMC PMC11992041
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Abstract

Clinical and genetic research links altered cholesterol metabolism with ALS development and progression, yet pinpointing specific pathomechanisms remain challenging. We investigated how cholesterol dysmetabolism interacts with protein aggregation, demyelination, and neuronal loss in ALS. Bulk RNAseq transcriptomics showed decreased cholesterol biosynthesis and increased cholesterol export in ALS mouse models (GA-Nes, GA-Camk2a GA-CFP, rNLS8) and patient samples (spinal cord), suggesting an adaptive response to cholesterol overload. Consequently, we assessed the efficacy of the cholesterol-binding drug 2-hydroxypropyl-β-cyclodextrin (CD) in a fast-progressing C9orf72 ALS mouse model with extensive poly-GA expression and myelination deficits. CD treatment normalized cholesteryl ester levels, lowered neurofilament light chain levels, and prolonged lifespan in female but not male GA-Nes mice, without impacting poly-GA aggregates. Single nucleus transcriptomics indicated that CD primarily affected oligodendrocytes, significantly restored myelin gene expression, increased density of myelinated axons, inhibited the disease-associated oligodendrocyte response, and downregulated the lipid-associated genes Plin4 and ApoD. These results suggest that reducing excess free cholesterol in the CNS could be a viable ALS treatment strategy.

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Authors
Rezaei, A., Kocsis-Jutka, V., Gunes, Z. I., Zeng, Q., Kislinger, G., Bauernschmitt, F., Isilgan, H. B., Parisi, L. R., Kaya, T., Franzenburg, S., Koppenbrink, J., Knogler, J., Arzberger, T., Farny, D., Nuscher, B., Katona, E., Dhingra, A., Yang, C., Gouna, G., LaClair, K. D., Janjic, A., Enard, W., Zhou, Q., Hagan, N., Ofengeim, D., Beltrán, E., Gokce, O., Simons, M., Liebscher, S., & Edbauer, D.
Affiliations
  • German Center for Neurodegenerative Diseases (DE)
  • Munich Cluster for Systems Neurology (DE)
  • University Hospital Bonn (DE)
  • Christian-Albrechts-Universität zu Kiel (DE)
  • LMU Klinikum (DE)
  • Ludwig-Maximilians-Universität München (DE)
  • Innsbruck Medical University (AT)
Corresponding author
Edbauer, Dieter
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-04-11
Volume
16
Issue
1
Pages
3442-3442
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-58634-4
PMC
PMC11992041
OpenAlex
W4409370654
Cited by
14
References
9
Citations by year
2026: 9 · 2025: 5
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
  • DZNE Pub (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Sanofi
  • European Commission (101057649, 101117710)
  • Deutsche Forschungsgemeinschaft (EXC 2145, 407495230, 390857198, 423957469)
  • HORIZON EUROPE Framework Programme (101057649)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
amyotrophic lateral sclerosis, C9orf72, cholesterol metabolism, oligodendrocytes, hydroxypropyl-β-cyclodextrin, myelination, lifespan extension, lipid metabolism, PLIN4, apolipoprotein D, neurofilament light chain, sex differences, single-nucleus transcriptomics, cholesterol export, myelin gene expression
MeSH terms
2-Hydroxypropyl-beta-cyclodextrin, C9orf72 Protein, Amyotrophic Lateral Sclerosis, Animals, Cholesterol, Disease Models, Animal, Female, Humans, Longevity, Male, Mice, Transgenic, Myelin Sheath, Oligodendroglia, Spinal Cord, Lipid Metabolism, Mice

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