Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease.
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 Fe(2+). 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.
Duan
Wenzhen
W
Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224, USA.
Ladenheim
Bruce
B
Cutler
Roy G
RG
Kruman
Inna I
II
Cadet
Jean Lud
JL
Mattson
Mark P
MP
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D002470:Cell Survival / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004032:Diet; D004298:Dopamine / Q000378:metabolism*; D004357:Drug Synergism; D005494:Folic Acid Deficiency / Q000150:complications / Q000503:physiopathology*; D006710:Homocysteine / Q000097:blood* / Q000494:pharmacology; D006801:Humans; D020138:Hyperhomocysteinemia / Q000209:etiology; D007501:Iron / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D012402:Rotenone / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D015415:Biomarkers; D012402:Rotenone; D006710:Homocysteine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007501:Iron; D004298:Dopamine