Transcription Factor Pitx3

The Parkinson's-Reversing Breakthrough

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Yet another clue to the factor(s) that render the dopamine neurons of the SNpc vulnerable to neurodegeneration in PD is obtained from the studies on the role of the transcription factor Pitx3 in aphakic mice. Aphakic mice have small eyes with no lens and a loss of development of the anterior chamber of the eye (57,58). The clinical features of the aphakic mice result from a deletion of a large segment of the promotor region, exon 1, and intron regions of the Pitx3 gene (58). In addition to the ophthalmic dysgenesis, aphakic mice exhibit degeneration of dopamine neurons of the SNpc cells during development. Pitx3 expression is localized to TH-immunoreactivity. Pitx3 is necessary for the expression of TH as well as continued maintenance of TH expression, even during the rest of the life of midbrain dopamine neurons. Accordingly, Pitx3 is expressed during ontogenesis of dopamine neurons as well as throughout the rest of the life of the midbrain dopamine neurons in rodents and humans (59). The dopamine neurons that express Pitx3 also express the neuroprotective calcium binding protein calbindin. The number of Pitx + calbindin cells is much higher in the VTA (43%) than in the SNpc (16%). The level of Pitx3 mRNA is six times higher in the VTA neurons than in the SNpc and that of Calbindin is four times higher in the VTA than the SNpc. Within the SNpc, 84% of the cells that express Pitx3 are CB negative (60).

Even though Pitx3 is expressed in all of the dopamine neurons of the midbrain during ontogenesis, the SNpc neurons degenerate significantly and selectively and the mesostriatal pathway terminating in the dorsolateral striatum also degenerates. The dopaminergic neurons of the VTA and their connectivity to the limbic striatum remain intact (61-64). With a profound loss of dopaminergic neurons of the SNpc, the levels of dopamine in the dorsal motor striatum are reduced to 10% of the level noted in the wild type (62). These aphakic mice demonstrate slow movements and shorter steps as in human PD (63,65,66), and these motor difficulties are easily reversed by the administration of levodopa (65,66). The intensity of expression of Pitx3 in 6-OHDA-induced PD in animals and in human mesencephalic dopamine neurons is significantly low (59).

The neurochemical changes noted in the mesencephalic dopamine neurons of the aphakic mice have several similarities to the neuropathology that is noted in human PD. In both conditions, there is a significant and preferential loss of dopamine neurons of the SNpc; the level of expression of Pitx3 in the SNpc neurons is very low; the degenerating neurons are mostly CB negative neurons; and a greater than 80% loss of dopamine in the dorsolateral sensory-motor striatum leads to significant bradykinesia that is easily reversed by levodopa.

The combined effects of a lower number of SNpc dopamine neurons expressing very low levels of Pitx3 and calbindin may be a factor in the increased vulnerability of SNpc neurons to neurodegeneration.

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