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| Home > Publications Database > Dataset: Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mouse model |
| Home > Publications Database > Dataset: Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mouse model |
| Dataset | DZNE-2025-00421 |
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2025
Gene Expression Omnibus
Abstract: Summary: These sequences support the following paper 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-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.” Overall design: GA-Nes mice (LaClair et al, Acta Neuropathologica 2020) and littermate controls were treated with the cholesterol sequestering drug 2-hydroxypropyl-β-cyclodextrin (CD) or vehicle control from P21 (daily subcutaneous treatment) and harvested on P40. We aim to investigate the mechanisms of lifespan extension and neurofilament reduction with CD treatment in female mice. Includes 15 samples.
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