Cystamine increases L-cysteine levels in Huntington's disease transgenic mouse brain and in a PC12 model of polyglutamine aggregation

被引:116
作者
Fox, JH
Barber, DS
Singh, B
Zucker, B
Swindell, MK
Norflus, F
Buzescu, R
Chopra, R
Ferrante, RJ
Kazantsev, A
Hersch, SM
机构
[1] Massachusetts Gen Hosp, Dept Neurol, Massgen Inst Neurodegenerat Dis, Charlestown, MA USA
[2] Univ Florida, Ctr Environm Hlth & Toxicol, Gainesville, FL USA
[3] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA
[4] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA
[5] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA
[6] Bedford VA Med Ctr, Ctr Geriatr Res Educ & Clin, Bedford, MA USA
关键词
cystamine; glutathione; Huntington's disease; L-cysteine; neuroprotection; oxidative stress;
D O I
10.1111/j.1471-4159.2004.02726.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Cystamine, a small disulfide-containing chemical, is neuroprotective in a transgenic mouse and a Drosophila model of Huntington's disease (HD) and decreases huntingtin aggregates in an in vitro model of HD. The mechanism of action of cystamine in these models is widely thought to involve inhibition of transglutaminase mediated cross-linking of mutant huntingtin in the process of aggregate formation/stabilization. In this study we show that cystamine, both in vitro and in a transgenic mouse model of HD (R6/2), increases levels of the cellular antioxidant L-cysteine. Several oxidative stress markers increase in HD brain. We provide further evidence of oxidative stress in mouse HD by demonstrating compensatory responses in R6/2 HD brains. We found age-dependent increases in forebrain glutathione (GSH), and increased levels of transcripts coding for proteins involved in GSH synthesis and detoxification pathways, as revealed by quantitative PCR analysis. Given the general importance of oxidative stress as a mediator of neurodegeneration we propose that an increase in brain L-cysteine levels could be protective in HD. Furthermore, cystamine was dramatically protective against 3-nitropropionic acid-induced striatal injury in mice. We suggest that cystamine's neuroprotective effect in HD transgenic mice results from pleiotropic effects that include transglutaminase inhibition and antioxidant activity.
引用
收藏
页码:413 / 422
页数:10
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