Endoplasmic Reticulum Stress as a Mediator of Neurotoxin-Induced Dopamine Neuron Death
Abstract
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 model of parkinsonism. Assessment of the functional significance of CHOP expression by study of CHOP null mice has shown that in the 6OHDA model immature animals do not have diminished apoptosis, but mature ones do. The null mutation does not, however, protect dopamine neurons in the chronic MPTP model. We have assessed these models for other markers of ER stress. We have performed Northern and in situ hybridization analysis of BiP, and RT-PCR/Southern analysis of the XBP-1 splice variant. Neither is upregulated in these models. We therefore conclude that while 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. A complete manuscript reporting our findings has been submitted and conditionally accepted by the Journal of Neurochemistry. Since our last progress report, we have begun our studies of caspase-12 mice in the adult 6OHDA model.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2005
- Accession Number
- ADA437720
Entities
People
- Robert E Burke
Organizations
- Columbia University