title: Gene-environment interaction models to unmask susceptibility mechanisms in Parkinson's disease.
abstract: Lipoxygenase (LOX) activity has been implicated in neurodegenerative disorders such as Alzheimer's disease, but its effects in Parkinson's disease (PD) pathogenesis are less understood. Gene-environment interaction models have utility in unmasking the impact of specific cellular pathways in toxicity that may not be observed using a solely genetic or toxicant disease model alone. To evaluate if distinct LOX isozymes selectively contribute to PD-related neurodegeneration, transgenic (i.e. 5-LOX and 12/15-LOX deficient) mice can be challenged with a toxin that mimics cell injury and death in the disorder. Here we describe the use of a neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces a nigrostriatal lesion to elucidate the distinct contributions of LOX isozymes to neurodegeneration related to PD. The use of MPTP in mouse, and nonhuman primate, is well-established to recapitulate the nigrostriatal damage in PD. The extent of MPTP-induced lesioning is measured by HPLC analysis of dopamine and its metabolites and semi-quantitative Western blot analysis of striatum for tyrosine hydroxylase (TH), the rate-limiting enzyme for the synthesis of dopamine. To assess inflammatory markers, which may demonstrate LOX isozyme-selective sensitivity, glial fibrillary acidic protein (GFAP) and Iba-1 immunohistochemistry are performed on brain sections containing substantia nigra, and GFAP Western blot analysis is performed on striatal homogenates. This experimental approach can provide novel insights into gene-environment interactions underlying nigrostriatal degeneration and PD.
authors.affiliation: Center for Health Sciences, SRI International.
authors.forename: Vivian P
authors.initials: VP
authors.lastname: Chou
authors.forename: Novie
authors.initials: N
authors.lastname: Ko
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Holman
authors.forename: Amy B
authors.initials: AB
authors.lastname: Manning-Boğ
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D007527:Isoenzymes; D008084:Lipoxygenase / Q000378:metabolism*; D051379:Mice; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics*; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
chemical_list: D007527:Isoenzymes; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008084:Lipoxygenase