Impairment of mitochondrial DNA repair enzymes against accumulation of 8-oxo-guanine in the spinal motor neurons of amyotrophic lateral sclerosis.

Oxidative stress plays an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). In the present study, we investigated the expression of two major human enzymes that prevent errors caused by 8-oxoguanine (8-oxoG), a mitochondrial form of 8-oxoG DNA glycosylase (hOGG1) and oxidized purine nucleoside triphosphatase (hMTH1). We also investigated the relationship between their expression and the 8-oxoG accumulation observed in the large motor neurons of the lumbar spinal cord in seven cases of adult onset sporadic ALS, four cases of subarachnoid hemorrhage (SAH) and four control cases. 8-oxoG immunoreactivity increased in most large motor neurons in both the ALS and SAH cases. However, the large motor neurons in the control cases often lacked hOGG1 immunoreactivity, although some neurons expressed hOGG1 in either homogeneous or fine granular patterns. In SAH cases, most large motor neurons showed a fine granular pattern proportional to the increased 8-oxoG immunoreactivity. However, only half of the remaining motor neurons in ALS expressed hOGG1 in the fine granular pattern, and the rest did not show any immunoreactivity. In addition, small aggregates of hMTH1 in the nuclei of the anterior horn cells were present in several ALS cases. Our results indicate that the oxidative damage accumulates in the mitochondria of motor neurons in ALS, and that hOGG1 does not repair the damage efficiently, which may lead to a loss of motor neurons in ALS.