MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Abstract

We previously reported that 8-oxoguanine (8-oxoG) accumulates in the cytoplasm of dopamine neurons in the substantia nigra of patients with Parkinson's disease and the expression of MTH1 carrying an oxidized purine nucleoside triphosphatase activity increases in these neurons, thus suggesting that oxidative damage in nucleic acids is involved in dopamine neuron loss. In the present study, we found that levels of 8-oxoG in cellular DNA and RNA increased in the mouse nigrostriatal system during the tyrosine hydroxylase (TH)-positive dopamine neuron loss induced by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MTH1-null mice exhibited a greater accumulation of 8-oxoG in mitochondrial DNA accompanied by a more significant decrease in TH and dopamine transporter immunoreactivities in the striatum after MPTP administration, than in wild-type mice. We thus demonstrated that MTH1 protects the dopamine neurons from oxidative damage in the nucleic acids, especially in the mitochondrial DNA of striatal nerve terminals of dopamine neurons.

The Flavonoids Ameliorates: Protective Mechanisms in Neurodegenerative Diseases

“…It is demonstrated in cell cultures and mice that a deficiency in MTH1, an oxidized purine nucleoside triphos-phatase, is strongly associated with the accumulation of 2-deoxy-8-oxoguanosine triphosphate in both nuclear and mitochondrial DNA, thus contributing to the increase of ROS from oxidative stress 7 . These findings have been supported in studies involving human Parkinson's disease patients that show that MTH1 suppresses cell death caused by oxidative stress [8][9] . It is evident that ROS from oxidative failures play a significant role in Parkinson's disease.…”

Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs

“…We have also demonstrated that 8-oxoG accumulation in mtDNA of striatal dopaminergic nerve terminals triggers their retrograde degeneration in a mouse model of PD (Yamaguchi et al, 2006). We therefore propose that an accumulation of 8-oxoG in mtDNA under oxidative stress causes mitochondrial dysfunction and activation of the calpain-cathepsin pathway, ending in neuronal loss (Figure 8).…”

“…MTH1-null mice exhibited a strong accumulation of 8-oxoG in mtDNA of striatal nerve terminals of dopamine neurons, accompanied by the increased degeneration of these terminals after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration (Yamaguchi et al, 2006). Furthermore, in MTH1-null mouse embryonic fibroblasts (MEFs), accumulation of 8-oxoG in cellular DNA was induced by H 2 O 2 , resulting in mitochondrial dysfunction and finally cell death (Yoshimura et al, 2003).…”

Paroxetine Prevents Loss of Nigrostriatal Dopaminergic Neurons by Inhibiting Brain Inflammation and Oxidative Stress in an Experimental Model of Parkinson’s Disease

“…In MPTP mice, DA neuronal cell death is accompanied by increased levels of 8-OHdG, a marker of oxidative nucleic acid damage (37). To determine whether paroxetine prevented MPTPinduced oxidative damage to DNA in the SN, we immunostained for 8-OHdG.…”