TY - JOUR
T1 - Correction of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice
AU - Rezaei, Ali
AU - Kocsis-Jutka, Virág
AU - Gunes, Zeynep I.
AU - Zeng, Qing
AU - Kislinger, Georg
AU - Bauernschmitt, Franz
AU - Isilgan, Huseyin Berkcan
AU - Parisi, Laura R.
AU - Kaya, Tuğberk
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 D.
AU - Janjic, Aleksandar
AU - Enard, Wolfgang
AU - Zhou, Qihui
AU - Hagan, Nellwyn
AU - Ofengeim, Dimitry
AU - Beltrán, Eduardo
AU - Gokce, Ozgun
AU - Simons, Mikael
AU - Liebscher, Sabine
AU - Edbauer, Dieter
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
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.
UR - https://www.scopus.com/pages/publications/105003323827
U2 - 10.1038/s41467-025-58634-4
DO - 10.1038/s41467-025-58634-4
M3 - Article
C2 - 40216746
AN - SCOPUS:105003323827
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3442
ER -