Cystamine and cysteamine prevent 3-NP-induced mitochondrial depolarization of Huntington's disease knock-in striatal cells

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 (S...

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Published in:The European journal of neuroscience 2006-04, Vol.23 (7), p.1701-1710
Main Authors: Mao, Zhengkuan, Choo, Yeun Su, Lesort, Mathieu
Format: Article
Language:English
Subjects:
3-nitropropionic acid
Animals
Cell Death - drug effects
Cell Line
Clone Cells
Corpus Striatum - cytology
Cystamine - pharmacology
Cysteamine - pharmacology
Electron Transport Complex II - antagonists & inhibitors
glutathione
Glutathione - metabolism
Huntingtin Protein
Huntington's disease
Membrane Potentials
Mice
Mice, Mutant Strains
mitochondria
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondria - physiology
Mitochondrial Membranes - physiology
Mutation
Nerve Tissue Proteins - genetics
Nitro Compounds - pharmacology
Nuclear Proteins - genetics
oxidative stress
Propionates - pharmacology
striatal cell culture
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Summary: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 µm cystamine and completely inhibited by 250 µm cystamine. Similar results were obtained using cysteamine (50–500 µm). 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 µm in combination with cystamine (250 µm) or cysteamine (250 µm) 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.
ISSN:0953-816X
1460-9568
DOI:10.1111/j.1460-9568.2006.04686.x