Signaling Pathways that Mediate Neurotoxin-Induced Death of Dopamine Neurons
Abstract
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). JNK/c-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 JNK/c-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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2005
- Accession Number
- ADA447899
Entities
People
- Dan A. Linseman
- Kim Heidenreich
Organizations
- University of Colorado Health