ACTIVATION OF JNK PATHWAY AND INDUCTION OF APOPTOSIS BY MANGANESE IN PC12 CELLS

Manganese is known to induce neurological disorders similar to parkins onisms. A dopamine deficiency has been demonstrated in Parkinson's dis ease and in chronic manganese poisoning, suggesting that the mechanism s underlying the neurotoxic effects of the metal ion are related to a functional abnormality of the extrapyramidal system. However, the deta ils have yet to be elucidated. Here we report that manganese causes ch aracteristic internucleosomal DNA fragmentation, a biochemical hallmar k of apoptosis, in PC12 cells. It was transcription dependent, relativ ely specific for manganese, and blocked in Bcl-2-overexpressed PC12 ce lls, The results indicate that apoptosis may play a role in the dopami nergic neurotoxicity associated with manganese, the first metal to be reported to induce this form of cell death. The early biochemical even ts show the impairment of energy metabolism, and the process may requi re new synthesis of proteins such as c-Fos and c-Jun. In addition, man ganese induces phosphorylation of c-Jun at Ser(63) and Ser(73) and SEK 1/MKK4 (c-Jun N-terminal kinase kinase) at Thr(258) and tyrosine phosp horylation of several proteins. These results indicate that manganese activates specific signal cascades including the c-Jun N-terminal kina se pathway,