Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice
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. Bu...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58634-4 |
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| author | Ali Rezaei Virág Kocsis-Jutka Zeynep I. Gunes Qing Zeng Georg Kislinger Franz Bauernschmitt Huseyin Berkcan Isilgan Laura R. Parisi Tuğberk Kaya Sören Franzenburg Jonas Koppenbrink Julia Knogler Thomas Arzberger Daniel Farny Brigitte Nuscher Eszter Katona Ashutosh Dhingra Chao Yang Garyfallia Gouna Katherine D. LaClair Aleksandar Janjic Wolfgang Enard Qihui Zhou Nellwyn Hagan Dimitry Ofengeim Eduardo Beltrán Ozgun Gokce Mikael Simons Sabine Liebscher Dieter Edbauer |
| author_facet | Ali Rezaei Virág Kocsis-Jutka Zeynep I. Gunes Qing Zeng Georg Kislinger Franz Bauernschmitt Huseyin Berkcan Isilgan Laura R. Parisi Tuğberk Kaya Sören Franzenburg Jonas Koppenbrink Julia Knogler Thomas Arzberger Daniel Farny Brigitte Nuscher Eszter Katona Ashutosh Dhingra Chao Yang Garyfallia Gouna Katherine D. LaClair Aleksandar Janjic Wolfgang Enard Qihui Zhou Nellwyn Hagan Dimitry Ofengeim Eduardo Beltrán Ozgun Gokce Mikael Simons Sabine Liebscher Dieter Edbauer |
| author_sort | Ali Rezaei |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8202e2275a264a0cb71fc18fc336eb86 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-8202e2275a264a0cb71fc18fc336eb862025-08-20T03:10:10ZengNature PortfolioNature Communications2041-17232025-04-0116111710.1038/s41467-025-58634-4Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 miceAli Rezaei0Virág Kocsis-Jutka1Zeynep I. Gunes2Qing Zeng3Georg Kislinger4Franz Bauernschmitt5Huseyin Berkcan Isilgan6Laura R. Parisi7Tuğberk Kaya8Sören Franzenburg9Jonas Koppenbrink10Julia Knogler11Thomas Arzberger12Daniel Farny13Brigitte Nuscher14Eszter Katona15Ashutosh Dhingra16Chao Yang17Garyfallia Gouna18Katherine D. LaClair19Aleksandar Janjic20Wolfgang Enard21Qihui Zhou22Nellwyn Hagan23Dimitry Ofengeim24Eduardo Beltrán25Ozgun Gokce26Mikael Simons27Sabine Liebscher28Dieter Edbauer29German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)Munich Cluster of Systems Neurology (SyNergy)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)Munich Cluster of Systems Neurology (SyNergy)German Center for Neurodegenerative Diseases (DZNE)Sanofi, Rare and Neurologic DiseasesGerman Center for Neurodegenerative Diseases (DZNE)Institute of Clinical Molecular Biology, Kiel UniversityGerman Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)Center for Neuropathology and Prion Research, University Hospital, LMU MunichGerman Center for Neurodegenerative Diseases (DZNE)Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität MunichGerman Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)Anthropology and Human Genomics, Faculty of Biology, Ludwig-Maximilians Universität MünchenAnthropology and Human Genomics, Faculty of Biology, Ludwig-Maximilians Universität MünchenGerman Center for Neurodegenerative Diseases (DZNE)Sanofi, Rare and Neurologic DiseasesSanofi, Rare and Neurologic DiseasesMunich Cluster of Systems Neurology (SyNergy)Munich Cluster of Systems Neurology (SyNergy)German Center for Neurodegenerative Diseases (DZNE)Munich Cluster of Systems Neurology (SyNergy)German Center for Neurodegenerative Diseases (DZNE)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.https://doi.org/10.1038/s41467-025-58634-4 |
| spellingShingle | Ali Rezaei Virág Kocsis-Jutka Zeynep I. Gunes Qing Zeng Georg Kislinger Franz Bauernschmitt Huseyin Berkcan Isilgan Laura R. Parisi Tuğberk Kaya Sören Franzenburg Jonas Koppenbrink Julia Knogler Thomas Arzberger Daniel Farny Brigitte Nuscher Eszter Katona Ashutosh Dhingra Chao Yang Garyfallia Gouna Katherine D. LaClair Aleksandar Janjic Wolfgang Enard Qihui Zhou Nellwyn Hagan Dimitry Ofengeim Eduardo Beltrán Ozgun Gokce Mikael Simons Sabine Liebscher Dieter Edbauer Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice Nature Communications |
| title | Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice |
| title_full | Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice |
| title_fullStr | Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice |
| title_full_unstemmed | Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice |
| title_short | Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice |
| title_sort | correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly ga c9orf72 mice |
| url | https://doi.org/10.1038/s41467-025-58634-4 |
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