Molecular Mechanisms of Dopaime Receptor Mediated Neuroprotection
Final rept. 15 Jul 1999-15 Jul 2004
MOUNT SINAI SCHOOL OF MEDICINE NEW YORK
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Exposure to specific neurotoxins can cause Parkinsons disease by damaging dopamnergic neurons. These neurotoxins induce neuronal loss by apoptosis or cell death, which results from sequential signaling events, from the inducer of apoptosis to the ultimate execution of the cellular changes characteristic of this process. We provide evidence that structurally distinct classes of neurotoxins activate the tumor suppressor protein, p53 early after toxic insult to induce cell death. The protection observed with inhibition of p53 further confirmed that p53 activation is critical for the cell loss in response to neurotoxins. Thus, the p53 cascade, or factors upstream regulating p53 activation, can be used as targets for neuroprotective strategies in models of Parkinsons disease. The drugs acting on dopamine receptors are known to provide symptomatic benefits for Parkinsons disease, recent clinical trials suggest that they might also be neuroprotective. We find that dopamine agonists have robust, concentration-dependent antiapoptotic activity. The predominant signaling cascade mediating cytoprotection by the D2 receptor involves c-SrcEGFR transactivation by D2 receptor, activating PI 3-K and Akt. We also found that specific dopamine agonists stabilize distinct conformations of the D2 receptor that differ in their coupling to G-proteins and to a cytoprotective c-SrcEGFR-mediated PI-3KAkt pathway.
- Medicine and Medical Research