Tp53, a stress response gene, is involved in diverse cell death pathways and its activation is implicated in the pathogenesis of Parkinson's disease. However, whether the neuronal Tp53 protein plays a direct role in regulating dopaminergic(DA) neuronal cell death or neuronal terminal damage in different neurotoxican models is unknown. In our recent studies, in contrast to the global inhibition of Tp53 function by phar macological inhibitors and in traditional Tp53 knock-out mice, we examined the effects of DA-specific Tp53 gene deletion after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and methamphetamine exposure Our data suggests that the Tp53 gene might be involved in both neuronal apoptosis and neuronal termi nal damage caused by different neurotoxicants. Additional results from other studies also suggest that as a master regulator of many pathways that regulate apoptosis and synaptic terminal damage, it is possible tha Tp53 may function as a signaling hub to integrate different signaling pathways to mediate distinctive targe pathways. Tp53 protein as a signaling hub might be able to evaluate the microenvironment of neurons assess the forms and severities of injury incurred, and determine whether apoptotic cell death or neuro nal terminal degeneration occurs. Identification of the precise mechanisms activated in distinct neurona damage caused by different forms and severities of injuries might allow for development of specific Tp53 inhibitors or ways to modulate distinct downstream target pathways involved.
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