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Behavioral and histopathological consequences of paraquat intoxication in mice: Effects of α‐synuclein over‐expression
Author(s) -
Fernagut P.O.,
Hutson C.B.,
Fleming S.M.,
Tetreaut N.A.,
Salcedo J.,
Masliah E.,
Chesselet M.F.
Publication year - 2007
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20456
Subject(s) - paraquat , substantia nigra , tyrosine hydroxylase , pars compacta , alpha synuclein , dopaminergic , neuroprotection , locus coeruleus , parkinson's disease , transgene , biology , dopamine , genetically modified mouse , endocrinology , pharmacology , neuroscience , medicine , biochemistry , central nervous system , disease , gene
Genetic variability in the α‐synuclein gene and long‐term exposure to the pesticide paraquat constitute possible risk factors for sporadic Parkinson's disease. The goal of the present study was to further characterize the effects of paraquat in mice as a model of Parkinson's disease and to determine whether it acted synergistically with α‐synuclein over‐expression to cause nigrostriatal cell death or dysfunction. Paraquat (10 mg/kg i.p.) was administered once a week for 3 weeks to mice over‐expressing human α‐synuclein under the Thy1 promoter and their wild‐type littermates. The effect of paraquat on catecholaminergic neurons was reminiscent of that of Parkinson's disease, with preferential loss of dopaminergic neurons in the ventral tier of the substantia nigra pars compacta and loss of tyrosine hydroxylase staining in the locus coeruleus. α‐Synuclein over‐expression did not increase paraquat‐induced cell loss, and paraquat did not worsen the behavioral deficits observed in the transgenic mice. However, paraquat markedly increased proteinase‐K‐resistant α‐synuclein aggregates in substantia nigra of the transgenic mice. The data further validate the use of paraquat to model Parkinson's disease in mice and show that although paraquat and α‐synuclein over‐expression act synergistically to increase protein aggregation in vivo, this interaction does not result in short‐term neuroprotection or increased vulnerability of nigrostriatal neurons. Synapse 61:991–1001, 2007. © 2007 Wiley‐Liss, Inc.