TY  - JOUR
AU  - Rezaei, Ali
AU  - Kocsis-Jutka, Virág
AU  - Günes, Zeynep Irem
AU  - Zeng, Qing
AU  - Kislinger, Georg
AU  - Bauernschmitt, Franz
AU  - Isilgan, Huseyin Berkcan
AU  - Parisi, Laura R
AU  - Kaya, Tugberk
AU  - Franzenburg, Sören
AU  - Koppenbrink, Jonas
AU  - Knogler, Julia
AU  - Arzberger, Thomas
AU  - Farny, Daniel
AU  - Nuscher, Brigitte
AU  - Katona, Eszter
AU  - Dhingra, Ashutosh
AU  - Yang, Chao
AU  - Gouna, Garyfallia
AU  - LaClair, Katherine
AU  - Janjic, Aleksandar
AU  - Enard, Wolfgang
AU  - Zhou, Qihui
AU  - Hagan, Nellwyn
AU  - Ofengeim, Dimitry
AU  - Beltrán, Eduardo
AU  - Gökce, Ozgun
AU  - Simons, Mikael
AU  - Liebscher, Sabine
AU  - Edbauer, Dieter
TI  - Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2025-00517
SP  - 3442
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Female
KW  - Mice
KW  - Oligodendroglia: metabolism
KW  - Oligodendroglia: drug effects
KW  - Lipid Metabolism: drug effects
KW  - Lipid Metabolism: genetics
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Amyotrophic Lateral Sclerosis: drug therapy
KW  - Amyotrophic Lateral Sclerosis: pathology
KW  - C9orf72 Protein: genetics
KW  - C9orf72 Protein: metabolism
KW  - Disease Models, Animal
KW  - Male
KW  - Cholesterol: metabolism
KW  - Humans
KW  - 2-Hydroxypropyl-beta-cyclodextrin: pharmacology
KW  - Mice, Transgenic
KW  - Myelin Sheath: metabolism
KW  - Spinal Cord: metabolism
KW  - Spinal Cord: pathology
KW  - Longevity: drug effects
KW  - Longevity: genetics
KW  - C9orf72 Protein (NLM Chemicals)
KW  - Cholesterol (NLM Chemicals)
KW  - 2-Hydroxypropyl-beta-cyclodextrin (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40216746
C2  - pmc:PMC11992041
DO  - DOI:10.1038/s41467-025-58634-4
UR  - https://pub.dzne.de/record/277990
ER  -