Endoplasmic Reticulum Stress as a Mediator of Neurotoxin-Induced Dopamine Neuron Death

摘要

The molecular processes of programmed cell death (PCD) are important mediators of neural degeneration in Parkinson's disease (PD). The goal of this proposal is to examine in living animals the possible role of ER stress, a mediator of PCD, in dopamine neuron death. This is being done by the study of mice with targeted deletions of CHOP and caspase-12, mediators of ER stress- induced apoptosis. We have demonstrated that CHOP is universally expressed in neurotoxin models of parkinsonism. Assessment of the functional significance of CHOP expression by study of CHOP null mice has shown that in the adult 6OHDA model there is diminished apoptosis. The null mutation does not, however, protect dopamine neurons in the chronic MPTP model. We therefore conclude that CHOP is expressed and uniquely plays a functional role in the adult 6OHDA model. It may do so either in response to ER stress, or to oxidative stress. Since our last progress report, we have completed our studies of caspase-12 mice in the adult 6OHDA model. These studies have shown that caspase-12 mice are not protected from 6OHDA; they do not show a diminished level of apoptosis, and they do not show an increased survival of dopaminergic neurons. Since caspase-12 is a proven critical mediator of PCD due to ER stress, these results would suggest that the upregulation of CHOP in the 6OHDA model is not mediated by ER stress, but rather oxidative insult. In the final year of this award, we intend to determine where CHOP acts in the molecular pathways of PCD in relation to signaling by c-jun phosphorylation. This will be done by examining the effect on CHOP expression of null mutations in both JNK2 and JNK3.