Signaling Pathways that Mediate Neurotoxin-Induced Death of Dopamine Neurons
Final rept. 1 Nov 2003-31 Oct 2008
COLORADO UNIV HEALTH SCIENCES CENTER AURORA CO
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Parkinson s disease PD is characterized by progressive loss of dopaminergic neurons in the nigrostriatal pathway resulting in significant motor dysfunction. The pathology of PD is mimicked by exposure to 1-methyl-4-phenyl-1,2,3,tetrahydropyridine MPTP or the pesticide rotenone. These neurotoxins inhibit complex I of the mitochondrial respiratory chain resulting in the production of reactive oxygen species ROS and increased cytosolic calcium. We hypothesize that ROS promotes opening of the mitochondrial permeability transition pore which triggers the death pathway. In parallel, increases in cytosolic calcium leads to oxidative stress and activation of c-Jun-NH2-terminal kinase JNK. JNKc-Jun signaling augments activation of the mitochondrial apoptotic cascade by suppressing Bcl-2 pro-survival signals via phosphorylation of Bcl-2 or transcription of the BH3-only, Bcl-2 antagonist Bim. The interactions between the oxidative stress pathway, the JNKc-Jun signaling cascade, and the mitochondrial apoptotic machinery ultimately determine the fate of dopamine neurons. We will utilize primary ventral mesencephalic cultures obtained from E15 embryonic rats to investigate our hypothesis. The data obtained should lead to the identification of promising therapeutic strategies to slow or halt the dopaminergic neurodegeneration that occurs during progression of PD.
- Medicine and Medical Research