Degenerative mechanism in dopaminergic neurons
The degenerative mechanisms of dopaminergic cells in Parkinsona??s disease (PD) remained elusive even after many years of research. However, many have hypothesized that the cell deaths in PD are via apoptosis and in particularly, by the mitochondrial-mediated apoptotic pathway. As such, the purpose of this study was to investigate validity of this hypothesis using a mouse dopaminergic cell line of mesencephalic origin, MN9D, and the Parkinsonism-causing neurotoxin MPP+ (1-methyl-4-phenylpyridinium ion), as a model. In this study, necrosis did not appear to be involved. Characteristics of apoptosis such as chromatin condensation were evident. However, caspase-3 did not appear to mediate cell death upon MPP+ challenge in this cell line, therefore rejecting the widely accepted hypothesis that the mitochondrial-mediated pathway is involved. Instead, the use of specific caspase inhibitors showed data of caspase-8, caspase-6 and caspase-7 playing a part in the death pathway. A time-course study also suggested the activation of caspase-8, followed by the activation of the downstream caspase-6 and caspase-7. Further investigation also demonstrated a time-dependent release of AIF, a mitochondrial-located protein capable of inducing cell death, into the cytosol. This suggests that AIF might indeed be a part of this alternative death pathway induced in MPP+-challenged MN9D cells. Preliminary results also showed the potential involvement of stress proteins such as JNKs in MN9D cell death. The results obtained in this study seem to open whole new possibilities of alternative apoptotic pathways that do not agree with the current hypothesis. Therefore, the use of therapeutic agents targeting the mitochondria or the mitochondrial-mediated apoptotic pathways should be reviewed.
Parkinson's Disease Dopaminergic Neurons MPP+ Apoptosis
Networked Digital Library of Theses and Dissertations