Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic, neurons in models of Parkinson's disease

被引:328
作者
Duan, W
Ladenheim, B
Cutler, RG
Kruman, II
Cadet, JL
Mattson, MP
机构
[1] NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA
[2] NIDA, Intramural Res Program, Mol Neuropsychiat Sect, Baltimore, MD USA
[3] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA
关键词
apoptosis; dopamine; folic acid; 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine; rotenone; substantia nigra;
D O I
10.1046/j.0022-3042.2001.00676.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
Although the cause of Parkinson's disease (PD) is unknown, data suggest roles for environmental factors that may sensitize dopaminergic neurons to age-related dysfunction and death. Based upon epidemiological data suggesting roles for dietary factors in PD and other age-related neurodegenerative disorders, we tested the hypothesis that dietary folate can modify vulnerability of dopaminergic neurons to dysfunction and death in a mouse model of PD. We report that dietary folate deficiency sensitizes mice to MPTP-induced PD-like pathology and motor dysfunction. Mice on a folate-deficient diet exhibit elevated levels of plasma homocysteine. When infused directly into either the substantia nigra or striatum, homocysteine exacerbates MPTP-induced dopamine depletion, neuronal degeneration and motor dysfunction. Homocysteine exacerbates oxidative stress, mitochondrial dysfunction and apoptosis in human dopaminergic cells exposed to the pesticide rotenone or the pro-oxidant Fe2+. The adverse effects of homocysteine on dopaminergic cells is ameliorated by administration of the antioxidant uric acid and by an inhibitor of poly (ADP-ribose) polymerase. The ability of folate deficiency and elevated homocysteine levels to sensitize dopaminergic neurons to environmental toxins suggests a mechanism whereby dietary folate may influence risk for PD.
引用
收藏
页码:101 / 110
页数:10
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