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000277990 1001_ $$0P:(DE-2719)9000720$$aRezaei, Ali$$b0$$eFirst author$$udzne
000277990 245__ $$aCorrection of dysregulated lipid metabolism normalizes gene expression in oligodendrocytes and prolongs lifespan in female poly-GA C9orf72 mice.
000277990 260__ $$a[London]$$bSpringer Nature$$c2025
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000277990 520__ $$aClinical 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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000277990 650_7 $$2NLM Chemicals$$aC9orf72 Protein
000277990 650_7 $$097C5T2UQ7J$$2NLM Chemicals$$aCholesterol
000277990 650_7 $$01I96OHX6EK$$2NLM Chemicals$$a2-Hydroxypropyl-beta-cyclodextrin
000277990 650_2 $$2MeSH$$aAnimals
000277990 650_2 $$2MeSH$$aFemale
000277990 650_2 $$2MeSH$$aMice
000277990 650_2 $$2MeSH$$aOligodendroglia: metabolism
000277990 650_2 $$2MeSH$$aOligodendroglia: drug effects
000277990 650_2 $$2MeSH$$aLipid Metabolism: drug effects
000277990 650_2 $$2MeSH$$aLipid Metabolism: genetics
000277990 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000277990 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000277990 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: drug therapy
000277990 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: pathology
000277990 650_2 $$2MeSH$$aC9orf72 Protein: genetics
000277990 650_2 $$2MeSH$$aC9orf72 Protein: metabolism
000277990 650_2 $$2MeSH$$aDisease Models, Animal
000277990 650_2 $$2MeSH$$aMale
000277990 650_2 $$2MeSH$$aCholesterol: metabolism
000277990 650_2 $$2MeSH$$aHumans
000277990 650_2 $$2MeSH$$a2-Hydroxypropyl-beta-cyclodextrin: pharmacology
000277990 650_2 $$2MeSH$$aMice, Transgenic
000277990 650_2 $$2MeSH$$aMyelin Sheath: metabolism
000277990 650_2 $$2MeSH$$aSpinal Cord: metabolism
000277990 650_2 $$2MeSH$$aSpinal Cord: pathology
000277990 650_2 $$2MeSH$$aLongevity: drug effects
000277990 650_2 $$2MeSH$$aLongevity: genetics
000277990 7001_ $$0P:(DE-2719)9001588$$aKocsis-Jutka, Virág$$b1$$eFirst author$$udzne
000277990 7001_ $$0P:(DE-2719)2812248$$aGünes, Zeynep Irem$$b2
000277990 7001_ $$0P:(DE-2719)9002977$$aZeng, Qing$$b3$$eFirst author$$udzne
000277990 7001_ $$0P:(DE-2719)9000614$$aKislinger, Georg$$b4
000277990 7001_ $$aBauernschmitt, Franz$$b5
000277990 7001_ $$0P:(DE-2719)9002460$$aIsilgan, Huseyin Berkcan$$b6$$udzne
000277990 7001_ $$aParisi, Laura R$$b7
000277990 7001_ $$0P:(DE-2719)9000609$$aKaya, Tugberk$$b8
000277990 7001_ $$00000-0001-6374-4910$$aFranzenburg, Sören$$b9
000277990 7001_ $$0P:(DE-2719)9002770$$aKoppenbrink, Jonas$$b10$$udzne
000277990 7001_ $$0P:(DE-2719)9003347$$aKnogler, Julia$$b11$$udzne
000277990 7001_ $$0P:(DE-2719)2811333$$aArzberger, Thomas$$b12$$udzne
000277990 7001_ $$0P:(DE-2719)2812127$$aFarny, Daniel$$b13
000277990 7001_ $$0P:(DE-2719)9000236$$aNuscher, Brigitte$$b14
000277990 7001_ $$0P:(DE-2719)9001378$$aKatona, Eszter$$b15$$udzne
000277990 7001_ $$0P:(DE-2719)2811729$$aDhingra, Ashutosh$$b16$$udzne
000277990 7001_ $$0P:(DE-2719)9001838$$aYang, Chao$$b17$$udzne
000277990 7001_ $$0P:(DE-2719)9001859$$aGouna, Garyfallia$$b18
000277990 7001_ $$0P:(DE-2719)2811939$$aLaClair, Katherine$$b19
000277990 7001_ $$aJanjic, Aleksandar$$b20
000277990 7001_ $$aEnard, Wolfgang$$b21
000277990 7001_ $$0P:(DE-2719)2811347$$aZhou, Qihui$$b22
000277990 7001_ $$aHagan, Nellwyn$$b23
000277990 7001_ $$00000-0003-2348-3642$$aOfengeim, Dimitry$$b24
000277990 7001_ $$00000-0002-7266-4098$$aBeltrán, Eduardo$$b25
000277990 7001_ $$0P:(DE-2719)9002754$$aGökce, Ozgun$$b26$$udzne
000277990 7001_ $$0P:(DE-2719)2811642$$aSimons, Mikael$$b27
000277990 7001_ $$0P:(DE-2719)9000187$$aLiebscher, Sabine$$b28
000277990 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b29$$eLast author
000277990 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-025-58634-4$$gVol. 16, no. 1, p. 3442$$n1$$p3442$$tNature Communications$$v16$$x2041-1723$$y2025
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