Neuroprotective effect of long-term NDI1 gene expression in a chronic mouse model of Parkinson disorder.
Previously, we showed that the internal rotenone-insensitive nicotinamide adenine dinucleotide (NADH)-quinone oxidoreductase (NDI1) gene from Saccharomyces cerevisiae (baker's yeast) can be successfully inserted into the mitochondria of mice and rats and the expressed enzyme was found to be fully functional. In this study, we investigated the ability of the Ndi1 enzyme to protect the dopaminergic neurons in a chronic mouse model of Parkinson disorder. After expression of the NDI1 gene in the unilateral substantia nigra of male C57BL/6 mice for 8 months, a chronic Parkinsonian model was created by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) with probenecid and evaluated using neurochemical and behavioral responses 1-4 weeks post-MPTP/probenecid injection. We showed that expression of Ndi1 was able to significantly prevent the loss of dopamine and tyrosine hydroxylase as well as the dopaminergic transporters in the striatum of the chronic Parkinsonian mice. Behavioral assessment based on a methamphetamine-induced rotation test and spontaneous swing test further supported neurological preservation in the NDI1-treated Parkinsonian mice. The data presented in this study demonstrate a protective effect of the NDI1 gene in dopaminergic neurons, suggesting its therapeutic potential for Parkinson-like disorders.
Barber-Singh
Jennifer
J
The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, California 92037, USA.
Seo
Byoung Boo
BB
Nakamaru-Ogiso
Eiko
E
Lau
Yuen-Sum
YS
Matsuno-Yagi
Akemi
A
Yagi
Takao
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002908:Chronic Disease; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D011339:Probenecid / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C493237:Ndi1 protein, S cerevisiae; D018696:Neuroprotective Agents; D029701:Saccharomyces cerevisiae Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D042967:Electron Transport Complex I; D011339:Probenecid; D004298:Dopamine