title: Cystamine and cysteamine prevent 3-NP-induced mitochondrial depolarization of Huntington's disease knock-in striatal cells.
abstract: Abstract Cystamine significantly improved motor deficits and extended survival in mouse models of Huntington's disease (HD); however, the precise mechanism(s) by which cystamine and the related compound cysteamine are beneficial remain to be elucidated. Using clonal striatal cell lines from wild-type (STHdhQ7/HdhQ7) and mutant huntingtin knock-in (STHdhQ111/HdhQ111) mice, we have tested the hypothesis that cystamine and cysteamine could be beneficial by preventing the depolarization of mitochondria in cell cultures. Treatment with 3-nitroproprionic acid (3-NP), a mitochondrial complex II inhibitor, induces mitochondrial depolarization and cell death of mutant HD striatal cells but not of wild-type cells. The 3-NP-mediated decrease in the mitochondrial membrane potential was attenuated by 50 microm cystamine and completely inhibited by 250 microm cystamine. Similar results were obtained using cysteamine (50-500 microm). In addition, both cystamine and cysteamine significantly attenuated the 3-NP-induced cell death. Treatment of mutant HD striatal cells with 3-NP resulted in a robust decrease in the cellular and mitochondrial levels of glutathione (GSH) compared with cells exposed to the vehicle alone. Pre-treatment of the cells with cystamine and cysteamine completely prevented the 3-NP-mediated decrease in cellular and mitochondrial GSH levels. Incubation with L-buthionine (S,R) sulfoximine (BSO) 250 microm in combination with cystamine (250 microm) or cysteamine (250 microm) prior to being treated with 3-NP completely prevented the beneficial effects of cystamine and cysteamine on the 3-NP-mediated mitochondrial depolarization. These results demonstrate that cystamine and cysteamine prevent the 3-NP-induced mitochondrial depolarization of HD striatal cell cultures.
authors.affiliation: Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
authors.forename: Zhengkuan
authors.initials: Z
authors.lastname: Mao
authors.forename: Yeun Su
authors.initials: YS
authors.lastname: Choo
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lesort
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002999:Clone Cells; D003342:Corpus Striatum / Q000166:cytology; D003538:Cystamine / Q000494:pharmacology*; D003543:Cysteamine / Q000494:pharmacology*; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors*; D005978:Glutathione / Q000378:metabolism; D000071058:Huntingtin Protein; D008564:Membrane Potentials; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051336:Mitochondrial Membranes / Q000502:physiology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009574:Nitro Compounds / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics*; D011422:Propionates / Q000494:pharmacology*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009574:Nitro Compounds; D009687:Nuclear Proteins; D011422:Propionates; D003543:Cysteamine; D042963:Electron Transport Complex II; D005978:Glutathione; C015392:3-nitropropionic acid; D003538:Cystamine