Eckmann 2014 Mol Neurobiol

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Eckmann J, Clemens LE, Eckert SH, Hagl S, Yu-Taeger L, Bordet T, Pruss RM, Muller WE, Leuner K, Nguyen HP, Eckert GP (2014) Mitochondrial membrane fluidity is consistently increased in different models of Huntington disease: restorative effects of olesoxime. Mol Neurobiol 50:107-18.

» PMID: 24633813

Eckmann J, Clemens LE, Eckert SH, Hagl S, Yu-Taeger L, Bordet T, Pruss RM, Muller WE, Leuner K, Nguyen HP, Eckert GP (2014) Mol Neurobiol

Abstract: Huntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the huntingtin gene (HTT). One prominent target of the mutant huntingtin protein (mhtt) is the mitochondrion, affecting its morphology, distribution, and function. Thus, mitochondria have been suggested as potential therapeutic targets for the treatment of HD. Olesoxime, a cholesterol-like compound, promotes motor neuron survival and neurite outgrowth in vitro, and its effects are presumed to occur via a direct interaction with mitochondrial membranes (mtMs). We examined the properties of mtMs isolated from cell and animal models of HD as well as the effects of olesoxime on mtM fluidity and cholesterol levels. mtMs isolated from brains of aged Hdh Q111/Q111 knock-in mice showed a significant decrease in 1,6-diphenyl-hexatriene (DPH) anisotropy, which is inversely correlated with membrane fluidity. Similar increases in mtM fluidity were observed in striatal STHdh Q111/Q111 cells as well as in mtMs isolated from brains of BACHD transgenic rats. Treatment of STHdh cells with olesoxime decreased the fluidity of isolated mtMs. Decreased membrane fluidity was also measured in olesoxime-treated mtMs isolated from brains of HD knock-in mice. In both models, treatment with olesoxime restored HD-specific changes in mtMs. Accordingly, olesoxime significantly counteracted the mhtt-induced increase in mtM fluidity of mtMs isolated from brains of BACHD rats after 12 months of treatment in vivo, possibly by enhancing mtM cholesterol levels. Thus, olesoxime may represent a novel pharmacological tool to treat mitochondrial dysfunction in HD.

Keywords: BACHDrat, Huntington disease, Membrane cholesterol, Membrane fluidity, Mitochondrial membrane

O2k-Network Lab: DE Giessen Eckert GP


Labels: MiParea: mt-Membrane, Genetic knockout;overexpression  Pathology: Neurodegenerative 

Organism: Mouse, Rat 




HRR: Oxygraph-2k