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 -l,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 Bc 1-2 pro-survival signals via phosphorylation of Bc1-2 or transcription of the BH3-only, Bc1-2 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.
[1]
K. Heidenreich,et al.
Proteasome inhibition elicits a biphasic effect on neuronal apoptosis via differential regulation of pro-survival and pro-apoptotic transcription factors
,
2005,
Molecular and Cellular Neuroscience.
[2]
E. Kandel,et al.
Inhibition of Rac GTPase triggers a c‐Jun‐ and Bim‐dependent mitochondrial apoptotic cascade in cerebellar granule neurons
,
2005,
Journal of neurochemistry.
[3]
T. Laessig,et al.
Glycogen Synthase Kinase-3β Phosphorylates Bax and Promotes Its Mitochondrial Localization during Neuronal Apoptosis
,
2004,
The Journal of Neuroscience.
[4]
K. Heidenreich,et al.
Myocyte enhancer factor-2 transcription factors in neuronal differentiation and survival
,
2004,
Molecular Neurobiology.