| Research Abstract |
Parkinson's disease is one of the most common neurodegenerative disorders in the aged. To elucidate the mechanism of neural aging, we established the cellular model of PD with mitochondrial dysfunction. In Parkinson's disease, characteristic pathological features are the cell death of nigro-striatal dopamine neurons and the formation of Lewy bodies composed of oxidized proteins. Mitochondrial dysfunction and aggregation of abnormal proteins have been proposed to cause the pathological changes. However, the relation between these two factors remains to be clarified. The effect of mitochondrial dysfunction on the oxidative modification and accumulation of proteins were studied using an inhibitor of mitochondrial complex I, rotenone, and antibodies against acrolein- and dityrosine-modified proteins. Under the conditions inducing mainly apoptosis in neuroblastoma SH-SY5Y cells, rotenone markedly increased oxidized proteins, especially those modified with acrolein, even though increase in the intracellular reactive oxygen and nitrogen species was only transient and not so marked. In addition, the activity of proteasome system degrading oxidized proteins reduced profoundly after treatment with rotenone. The 20S β subunit of proteasome was modified with acrolein, to which other acrolein-modified proteins were found to bind, as shown by the co-precipitation with the antibody against 20S β subunit. These results suggest that mitochondrial dysfunction, especially decreased activity of complex I, may reduce proteasome activity through the oxidative modification of proteasome itself and the aggregation with other oxidized proteins. To confirm this hypothesis, postmortem human brains were analyzed. In parkinsonian brains, decrease in proteasome activity was observed. This mechanism might account for the accumulation of modified protein, and, at least partially, for cell death of the dopamine neurons in Parkinson's disease.
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