Neurochemical and motor changes in mice with combined mutations linked to Parkinson's disease.
Considerable evidence suggests that oxidative stress plays a role in the pathogenesis of Parkinson's disease (PD), the most prevalent neurodegenerative movement disorder. Reduced expression of aldehyde dehydrogenase-1 (ALDH1) and glutathione peroxidase-1 (GPX1), enzymes that function to detoxify aldehydes and hydroxyl radicals, respectively, has been reported in the substantia nigra of patients who died with PD. To determine whether deficiency in these two genes contributes to the pathogenesis of PD, mice were generated with homozygous null mutations of both Aldh1a1 (the murine homolog of ALDH1) and Gpx1 genes [knockout (KO) mice]. At 6 and 18 months of age, KO mice showed a significantly decreased latency to fall in the automated accelerating rotarod test and increased time to complete the pole test opamine levels were not altered; however, the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and the DOPAC/dopamine ratio were significantly reduced at 18 months of age. Proteins adducted with 4-hydroxynonenal, the end-product of lipid peroxidation, were increased in the. midbrain and striatum of KO mice at 6 and 18 months. In conclusion, dual mutations in Gpx1 and Aldh1a1 genes are associated with motor deficits and increased lipid peroxidation in adult mice.
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Xiang
X
Bai
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Margaret Chia-Ying
MC
Wey
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Paul Anthony
PA
Martinez
Department of Management Science and Statistics, College of Business, University of Texas at San Antonio , San Antonio , TX , USA.
Chao
C
Shi
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care Network, San Antonio, TX, USA.
Elizabeth
E
Fernandez
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care Network, San Antonio, TX, USA.
Randy
R
Strong
Glutathione peroxidase-1 (Gpx1); Parkinson’s disease; aldehyde; aldehyde dehydrogenase-1a1 (Aldh1a1); dopamine and its metabolites; knockout mice; lipid peroxidation; motor deficit; movement disorder; oxidative stress