Home > Publications Database > Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice. > print

001     277990
005     20250504001145.0
024 7 _ |a 10.1038/s41467-025-58634-4
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024 7 _ |a pmc:PMC11992041
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037 _ _ |a DZNE-2025-00517
041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Rezaei, Ali
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245 _ _ |a Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice.
260 _ _ |a [London]
|c 2025
|b Springer Nature
336 7 _ |a article
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336 7 _ |a Output Types/Journal article
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336 7 _ |a Journal Article
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|s 1745921458_15704
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336 7 _ |a ARTICLE
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520 _ _ |a 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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650 _ 7 |a C9orf72 Protein
|2 NLM Chemicals
650 _ 7 |a Cholesterol
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650 _ 7 |a 2-Hydroxypropyl-beta-cyclodextrin
|0 1I96OHX6EK
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Oligodendroglia: metabolism
|2 MeSH
650 _ 2 |a Oligodendroglia: drug effects
|2 MeSH
650 _ 2 |a Lipid Metabolism: drug effects
|2 MeSH
650 _ 2 |a Lipid Metabolism: genetics
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: genetics
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: metabolism
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: drug therapy
|2 MeSH
650 _ 2 |a Amyotrophic Lateral Sclerosis: pathology
|2 MeSH
650 _ 2 |a C9orf72 Protein: genetics
|2 MeSH
650 _ 2 |a C9orf72 Protein: metabolism
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Cholesterol: metabolism
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a 2-Hydroxypropyl-beta-cyclodextrin: pharmacology
|2 MeSH
650 _ 2 |a Mice, Transgenic
|2 MeSH
650 _ 2 |a Myelin Sheath: metabolism
|2 MeSH
650 _ 2 |a Spinal Cord: metabolism
|2 MeSH
650 _ 2 |a Spinal Cord: pathology
|2 MeSH
650 _ 2 |a Longevity: drug effects
|2 MeSH
650 _ 2 |a Longevity: genetics
|2 MeSH
700 1 _ |a Kocsis-Jutka, Virág
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700 1 _ |a Günes, Zeynep Irem
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700 1 _ |a Zeng, Qing
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700 1 _ |a Kislinger, Georg
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700 1 _ |a Bauernschmitt, Franz
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700 1 _ |a Isilgan, Huseyin Berkcan
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700 1 _ |a Parisi, Laura R
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700 1 _ |a Kaya, Tugberk
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700 1 _ |a Franzenburg, Sören
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700 1 _ |a Koppenbrink, Jonas
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700 1 _ |a Knogler, Julia
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700 1 _ |a Arzberger, Thomas
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700 1 _ |a Farny, Daniel
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700 1 _ |a Nuscher, Brigitte
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700 1 _ |a Katona, Eszter
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700 1 _ |a Dhingra, Ashutosh
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700 1 _ |a Yang, Chao
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700 1 _ |a Gouna, Garyfallia
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700 1 _ |a LaClair, Katherine
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700 1 _ |a Janjic, Aleksandar
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700 1 _ |a Enard, Wolfgang
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700 1 _ |a Zhou, Qihui
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700 1 _ |a Hagan, Nellwyn
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700 1 _ |a Ofengeim, Dimitry
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700 1 _ |a Beltrán, Eduardo
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700 1 _ |a Gökce, Ozgun
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700 1 _ |a Simons, Mikael
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700 1 _ |a Liebscher, Sabine
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700 1 _ |a Edbauer, Dieter
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773 _ _ |a 10.1038/s41467-025-58634-4
|g Vol. 16, no. 1, p. 3442
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