ORCID: https://orcid.org/0000-0001-8974-1304; Kocsis-Jutka, Virág; Gunes, Zeynep I. ORCID: https://orcid.org/0000-0002-4720-8226; Zeng, Qing ORCID: https://orcid.org/0000-0003-0574-1310; Kislinger, Georg ORCID: https://orcid.org/0000-0002-6559-7421; Bauernschmitt, Franz; Isilgan, Huseyin Berkcan ORCID: https://orcid.org/0000-0003-3369-1453; Parisi, Laura R.; Kaya, Tuğberk; Franzenburg, Sören ORCID: https://orcid.org/0000-0001-6374-4910; Koppenbrink, Jonas; Knogler, Julia; Arzberger, Thomas; Farny, Daniel; Nuscher, Brigitte; Katona, Eszter; Dhingra, Ashutosh; Yang, Chao; Gouna, Garyfallia ORCID: https://orcid.org/0000-0002-4644-8252; LaClair, Katherine D. ORCID: https://orcid.org/0000-0001-5052-2972; Janjic, Aleksandar ORCID: https://orcid.org/0000-0001-7180-5381; Enard, Wolfgang ORCID: https://orcid.org/0000-0002-4056-0550; Zhou, Qihui ORCID: https://orcid.org/0000-0001-5733-9820; Hagan, Nellwyn; Ofengeim, Dimitry ORCID: https://orcid.org/0000-0003-2348-3642; Beltrán, Eduardo ORCID: https://orcid.org/0000-0002-7266-4098; Gokce, Ozgun ORCID: https://orcid.org/0000-0001-6319-404X; Simons, Mikael ORCID: https://orcid.org/0000-0001-5329-192X; Liebscher, Sabine ORCID: https://orcid.org/0000-0001-5633-8981 und Edbauer, Dieter ORCID: https://orcid.org/0000-0002-7186-4653
(2025):
Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice.
In: Nature Communications, Vol. 16, 3442
[PDF, 5MB]
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.
| Item Type: | Journal article |
|---|---|
| Faculties: | Biology > Department Biology II Medicine > Biomedical Center Medicine > Institute of Neuropathology Medicine > Munich Cluster for Systems Neurology (SyNergy) Medicine > Medical Center of the University of Munich > Neurological Clinic and Polyclinic with Friedrich Baur Institute Medicine > Medical Center of the University of Munich > Clinic and Polyclinic for Psychiatry and Psychotherapy |
| Research Centers: | Munich Center for Neurosciences – Brain & Mind |
| Subjects: | 600 Technology > 610 Medicine and health |
| URN: | urn:nbn:de:bvb:19-epub-126010-9 |
| ISSN: | 2041-1723 |
| Language: | English |
| Item ID: | 126010 |
| Date Deposited: | 13. May 2025 14:00 |
| Last Modified: | 13. May 2025 14:00 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198 |
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