title: Mitochondrial membrane fluidity is consistently increased in different models of Huntington disease: restorative effects of olesoxime.
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 (MMs). We examined the properties of MMs isolated from cell and animal models of HD as well as the effects of olesoxime on MM fluidity and cholesterol levels. MMs 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 MM fluidity were observed in striatal STHdh Q111/Q111 cells as well as in MMs isolated from brains of BACHD transgenic rats. Treatment of STHdh cells with olesoxime decreased the fluidity of isolated MMs. Decreased membrane fluidity was also measured in olesoxime-treated MMs isolated from brains of HD knock-in mice. In both models, treatment with olesoxime restored HD-specific changes in MMs. Accordingly, olesoxime significantly counteracted the mhtt-induced increase in MM fluidity of MMs isolated from brains of BACHD rats after 12 months of treatment in vivo, possibly by enhancing MM cholesterol levels. Thus, olesoxime may represent a novel pharmacological tool to treat mitochondrial dysfunction in HD.
authors.affiliation: Department of Pharmacology, Biocenter, Goethe-University Campus Riedberg, Biocentre Geb. N260, R.1.09, Max-von-Laue Str. 9, 60438, Frankfurt, Germany.
authors.forename: Janett
authors.initials: J
authors.lastname: Eckmann
authors.forename: Laura E
authors.initials: LE
authors.lastname: Clemens
authors.forename: Schamim H
authors.initials: SH
authors.lastname: Eckert
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hagl
authors.forename: Libo
authors.initials: L
authors.lastname: Yu-Taeger
authors.forename: Thierry
authors.initials: T
authors.lastname: Bordet
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Pruss
authors.forename: Walter E
authors.initials: WE
authors.lastname: Muller
authors.forename: Kristina
authors.initials: K
authors.lastname: Leuner
authors.forename: Huu P
authors.initials: HP
authors.lastname: Nguyen
authors.forename: Gunter P
authors.initials: GP
authors.lastname: Eckert
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D002783:Cholestenones / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000188:drug therapy / Q000378:metabolism*; D008560:Membrane Fluidity / Q000187:drug effects*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects* / Q000378:metabolism; D051381:Rats
chemical_list: D002783:Cholestenones; C522838:olesoxime