Yet another clue toward the selective vulnerability of dopaminergic neurons in PD, especially the dopamine neurons of the SNpc more than the VTA neurons, is derived from the role played by uncoupling proteins (UCPs) in thermogenesis and obesity (67-71).
UCPs are localized in the inner membrane of the mitochondria and promote a "leak" of protons from the intermembrane space back into the matrix region of the mitochondria and may have a neuroprotective role by decreasing excess of reactive oxygen species (ROS) in the mitochondria (68,69). Five different UCPs (UCP1 to UCP5) have been identified (67). Of these, UCP1 (thermogenin), the most well-studied protein, is localized almost exclusively in the brown adipose tissue and UCP3 in skeletal and cardiac muscles play a major role in thermogenesis. UCP2, UCP4, and UCP5 are abundant in the brain. The distribution and role of UCP2 is better understood than for UCP4 or UCP5. The distribution pattern of mRNA for UCP4 and UCP5 in the brain remains to be studied.
The mRNA for UCP2 is prominently localized to neurons of the hypothalamic system and within the basal ganglia (72). UCP2 is localized to both the VTA and SNpc dopaminergic neurons. The intensity of expression of UCP2, as studied by realtime PCR in weaver mutant mice, is three times higher in the VTA dopamine neurons than the more laterally placed dopamine neurons of the SNpc (73). In MPTP models of PD in mice, over expression of UCP2 protects the midbrain dopaminergic neurons from MPTP-induced neurotoxic death and mutations of UCP2 (73,74). UCP5 knockdown mice have an increased sensitivity to MPTP-induced dopaminer-gic neuronal loss (75). The lower level of expression of UCP2 in the SNpc when compared to the VTA neurons might account for an increased vulnerability of the SNpc to neurodegeneration.
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