Journal Article

DZNE-2025-00517

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice.

Rezaei, A. (First author)DZNE* ; Kocsis-Jutka, V. (First author)DZNE* ; Günes, Z. I. ; Zeng, Q. (First author)DZNE* ; Kislinger, G.DZNE* ; Bauernschmitt, F. ; Isilgan, H. B.DZNE* ; Parisi, L. R. ; Kaya, T.DZNE* ; Franzenburg, S. ; Koppenbrink, J.DZNE* ; Knogler, J.DZNE* ; Arzberger, T.Extern* ; Farny, D.DZNE* ; Nuscher, B. ; Katona, E.DZNE* ; Dhingra, A.DZNE* ; Yang, C.DZNE* ; Gouna, G.DZNE* ; LaClair, K.DZNE* ; Janjic, A. ; Enard, W. ; Zhou, Q.DZNE* ; Hagan, N. ; Ofengeim, D. ; Beltrán, E. ; Gökce, O.Extern* ; Simons, M.DZNE* ; Liebscher, S. ; Edbauer, D. (Last author)DZNE*

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-58634-4

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.

Keyword(s): Animals (MeSH) ; Female (MeSH) ; Mice (MeSH) ; Oligodendroglia: metabolism (MeSH) ; Oligodendroglia: drug effects (MeSH) ; Lipid Metabolism: drug effects (MeSH) ; Lipid Metabolism: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Amyotrophic Lateral Sclerosis: drug therapy (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; C9orf72 Protein: genetics (MeSH) ; C9orf72 Protein: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Male (MeSH) ; Cholesterol: metabolism (MeSH) ; Humans (MeSH) ; 2-Hydroxypropyl-beta-cyclodextrin: pharmacology (MeSH) ; Mice, Transgenic (MeSH) ; Myelin Sheath: metabolism (MeSH) ; Spinal Cord: metabolism (MeSH) ; Spinal Cord: pathology (MeSH) ; Longevity: drug effects (MeSH) ; Longevity: genetics (MeSH) ; C9orf72 Protein ; Cholesterol ; 2-Hydroxypropyl-beta-cyclodextrin

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Contributing Institute(s):

1. Cell Biology of Neurodegeneration (AG Edbauer)
2. Molecular Neurobiology (AG Simons)
3. Adaptive Immunity in Neurodegeneration (AG Zhou)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2025

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