ORIGIN AND FUNCTIONAL CONSEQUENCES OF THE COMPLEX-I DEFECT IN PARKINSONS-DISEASE

The mitochondrial electron transport enzyme NADH:ubiquinone oxidoreduc tase (complex I), which is encoded by both mitochondrial DNA and nucle ar DNA, is defective in multiple tissues in persons with Parkinson's d isease (PD). The origin of this lesion and its role in the neurodegene ration of PD are unknown. To address these questions, we created an in vitro system in which the potential contributions of environmental to xins, complex I nuclear DNA mutations, and mitochondrial DNA mutations could be systematically analyzed. A clonal line of human neuroblastom a cells containing no mitochondrial DNA was repopulated with mitochond ria derived from the platelets of PD or control subjects. After 5 to 6 weeks in culture, these cytoplasmic hybrid (cybrid) cell lines were a ssayed for electron transport chain activities, production of reactive oxygen species, and sensitivity to induction of apoptotic cell death by 1-methyl-4-phenyl pyridinium (MPP+). In PD cybrids we found a stabl e 20% decrement in complex I activity, increased oxygen radical produc tion, and increased susceptibility to 1-methyl-4-phenyl pyridinium-ind uced programmed cell death. The complex I defect in PD appears to be g enetic, arising from mitochondrial DNA, and may play an important role in the neurodegeneration of PD by fostering reactive oxygen species p roduction and conferring increased neuronal susceptibility to mitochon drial toxins.