Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice
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.
Authors
- Ali Rezaei (ORCID: https://orcid.org/0000-0001-8974-1304)
- Thomas Arzberger
- Katherine D. LaClair (ORCID: https://orcid.org/0000-0001-5052-2972)
- Wolfgang Enard (ORCID: https://orcid.org/0000-0002-4056-0550)
- Dieter Edbauer (ORCID: https://orcid.org/0000-0002-7186-4653)
- Dimitry Ofengeim (ORCID: https://orcid.org/0000-0003-2348-3642)
- Huseyin Berkcan Isilgan (ORCID: https://orcid.org/0000-0003-3369-1453)
- Brigitte Nuscher (ORCID: https://orcid.org/0009-0000-4661-0742)
- Ashutosh Dhingra (ORCID: https://orcid.org/0000-0003-2997-7467)
- Qihui Zhou (ORCID: https://orcid.org/0000-0001-5733-9820)
- Aleksandar Janjic (ORCID: https://orcid.org/0000-0001-7180-5381)
- Virág Kocsis-Jutka
- Daniel Farny
- Georg Kislinger (ORCID: https://orcid.org/0000-0002-6559-7421)
- Laura R. Parisi (ORCID: https://orcid.org/0000-0003-4868-1426)
- Sabine Liebscher (ORCID: https://orcid.org/0000-0001-5633-8981)
- Sören Franzenburg (ORCID: https://orcid.org/0000-0001-6374-4910)
- Eduardo Beltrán (ORCID: https://orcid.org/0000-0002-7266-4098)
- Mikael Simons (ORCID: https://orcid.org/0000-0001-5329-192X)
- Tuğberk Kaya (ORCID: https://orcid.org/0000-0001-5926-8608)
- Zeynep I. Gunes (ORCID: https://orcid.org/0000-0002-4720-8226)
- Garyfallia Gouna (ORCID: https://orcid.org/0000-0002-4644-8252)
- Nellwyn Hagan
- Özgün Gökçe (ORCID: https://orcid.org/0000-0001-6319-404X)
- Eszter Katona
- Chao Yang (ORCID: https://orcid.org/0000-0002-8661-3275)
- Qing Zeng (ORCID: https://orcid.org/0000-0003-0574-1310)
- Jonas Koppenbrink
- Julia Knogler
- Franz Bauernschmitt
Institutions
- Innsbruck Medical University (AT)
- University Hospital Bonn (DE)
- German Center for Neurodegenerative Diseases (DE)
- LMU Klinikum (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Sanofi (United States) (US)
- Munich Cluster for Systems Neurology (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-11
- DOI
- https://doi.org/10.1038/s41467-025-58634-4
- Citations
- 6
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 6.99
Funders
- Sanofi
- Deutsche Forschungsgemeinschaft
- HORIZON EUROPE Framework Programme