title: Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease.
abstract: 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.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224, USA.
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Duan
authors.forename: Bruce
authors.initials: B
authors.lastname: Ladenheim
authors.forename: Roy G
authors.initials: RG
authors.lastname: Cutler
authors.forename: Inna I
authors.initials: II
authors.lastname: Kruman
authors.forename: Jean Lud
authors.initials: JL
authors.lastname: Cadet
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: 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
chemical_list: D015415:Biomarkers; D012402:Rotenone; D006710:Homocysteine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007501:Iron; D004298:Dopamine