The pathognomonic feature of idiopathic PD is the progressive degeneration of the dopaminergic neurons of the SNpc. The SNpc dopaminergic neurons degenerate early and more profoundly than any other melanin and nonmelanin containing neurons of the brain. The molecular characteristics of the SNpc dopamine neurons that make them more vulnerable to degeneration than the dopaminergic neurons of the VTA are that these cells:

■ are highly melanized;

■ do not express calcium binding proteins, especially calbindin DK28 or calretinin;

■ express low levels of VMAT2 mRNA;

■ express high levels of DAT mRNA and protein;,

■ undergo increased mitochondrial stress;

■ contain very high levels of mtDNA mutation;

■ express low levels of the transcription factor Pitx3 or Pitx3 is absent;

■ express low levels of UCP2, the protein that under normal conditions prevents excessive production of ROS in the mitochondria;

■ express a specific subtype of GIRK2 type of inward rectifying K channel receptor;

■ express a specific subtype of K-ATP channel that is activated.

The molecular and neurochemical factors that are unique to the dopamine neurons of the SNpc may either increase the susceptibility for PD or increase the vulnerability of these neurons to the neurotoxic effects of low-dose chronic exposure to either endogenous or exogenous neurotoxins.

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