Profiling genes related to mitochondrial function in mice treated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Since mitochondrial dysfunction plays an important role in the pathogenesis of dopaminergic neurodegeneration in Parkinson's disease, we determined the expression of genes related to mitochondrial function in the substantia nigra of mice treated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using a cDNA array. MPTP treatment significantly depleted striatal dopamine, but did not result in apparent neuronal loss in the substantia nigra at 3 and 18 days post-treatment. We also examined changes in genes in the hypothalamus, a region containing dopaminergic neurons that are relatively resistant to MPTP. Finally, we confirmed those genes identified by microarrays as differentially expressed in the substantia nigra but not in the hypothalamus using in situ hybridization. Our results demonstrated that MPTP significantly changed the expressions of six genes in nigral neurons, four of which were related to the mitochondrial electron transport chain: the NADH-ubiquinone oxidoreductase 13 kDa B subunit, the NADH-ubiquinone oxidoreductase MNLL subunit, cytochrome c, and the cytochrome c oxidase Va subunit. Two other differentially expressed genes were the dihydropyridine-sensitive L-type calcium channel alpha-2 subunit precursor and type III alpha-1 procollagen. None of these six genes are encoded by mitochondrial DNA. The potential significance of these gene alterations in the context of Parkinson's disease is discussed.
Gu
Guangyu
G
Division of Neuropathology, Department of Pathology, University of Washington School of Medicine, Box 359660, Harborview Medical Center, Seattle, WA 98104, USA.
Deutch
Ariel Y
AY
Franklin
Jeff
J
Levy
Shawn
S
Wallace
Douglas C
DC
Zhang
Jing
J
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D017931:DNA Primers; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics
D017931:DNA Primers; D015259:Dopamine Agents; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine