title: Mice with a partial deficiency of manganese superoxide dismutase show increased vulnerability to the mitochondrial toxins malonate, 3-nitropropionic acid, and MPTP.
abstract: There is substantial evidence implicating mitochondrial dysfunction and free radical generation as major mechanisms of neuronal death in neurodegenerative diseases. The major free radical scavenging enzyme in mitochondria is manganese superoxide dismutase (SOD2). In the present study we investigated the susceptibility of mice with a partial deficiency of SOD2 to the neurotoxins 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), 3-nitropropionic acid (3-NP), and malonate, which are commonly used animal models of Parkinson's and Huntington's disease. Heterozygous SOD2 knockout (SOD2(+/-)) mice showed no evidence of neuropathological or behavioral abnormalities at 2-4 months of age. Compared to littermate wild-type mice, mice with partial SOD2 deficiency showed increased vulnerability to dopamine depletion after systemic MPTP treatment and significantly larger striatal lesions produced by both 3-NP and malonate. SOD2(+/-) mice also showed an increased production of "hydroxyl" radicals after malonate injection measured with the salicylate hydroxyl radical trapping method. These results provide further evidence that reactive oxygen species play an important role in the neurotoxicity of MPTP, malonate, and 3-NP. These findings show that a subclinical deficiency in a free radical scavenging enzyme may act in concert with environmental toxins to produce selective neurodegeneration.
authors.affiliation: Neurochemistry Laboratory, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: O A
authors.initials: OA
authors.lastname: Andreassen
authors.forename: R J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: A
authors.initials: A
authors.lastname: Dedeoglu
authors.forename: D W
authors.initials: DW
authors.lastname: Albers
authors.forename: P
authors.initials: P
authors.lastname: Klivenyi
authors.forename: E J
authors.initials: EJ
authors.lastname: Carlson
authors.forename: C J
authors.initials: CJ
authors.lastname: Epstein
authors.forename: M F
authors.initials: MF
authors.lastname: Beal
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005841:Gentisates; D006579:Heterozygote; D006719:Homovanillic Acid / Q000378:metabolism; D062385:Hydroxybenzoates / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D008297:Male; D008314:Malonates; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism* / Q000633:toxicity; D009574:Nitro Compounds; D011422:Propionates; D020156:Salicylic Acid / Q000378:metabolism; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D005841:Gentisates; D062385:Hydroxybenzoates; D008314:Malonates; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D015102:3,4-Dihydroxyphenylacetic Acid; D017665:Hydroxyl Radical; C030290:malonic acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D013482:Superoxide Dismutase; D020156:Salicylic Acid; C015392:3-nitropropionic acid; C010925:2,5-dihydroxybenzoic acid; D004298:Dopamine; D006719:Homovanillic Acid