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Cystamine and cysteamine prevent 3‐NP‐induced mitochondrial depolarization of Huntington's disease knock‐in striatal cells
Author(s) -
Mao Zhengkuan,
Choo Yeun Su,
Lesort Mathieu
Publication year - 2006
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2006.04686.x
Subject(s) - cystamine , cysteamine , buthionine sulfoximine , glutathione , depolarization , programmed cell death , chemistry , mitochondrion , biochemistry , apoptosis , pharmacology , biology , microbiology and biotechnology , biophysics , enzyme
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 (ST Hdh Q7 / Hdh Q7 ) and mutant huntingtin knock‐in (ST Hdh Q111 / Hdh Q111 ) 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 µ m cystamine and completely inhibited by 250 µ m cystamine. Similar results were obtained using cysteamine (50–500 µ m ). 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 µ m in combination with cystamine (250 µ m ) or cysteamine (250 µ m ) 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.