<b><i>PITX3</i></b> and Risk for Parkinson's Disease: A Systematic Review and Meta-Analysis

Abstract

Background/Aims: Several single nucleotide polymorphisms (SNPs) in the PITX3 gene have been associated with the risk for Parkinson's disease (PD). We conducted a systematic review and a meta-analysis including all the studies published on the risk of PD related with these polymorphisms. Methods: The systematic review was done using several databases. Eligible studies were included in the meta-analysis that was carried out using Meta-DiSc 1.1.1 software. Heterogeneity between studies was tested using the Q-statistic. Results: The meta-analysis included eight association studies for the PITX3 rs3758549 SNP (4,052 PD patients, 3,949 controls), eight studies for the PITX3 rs2281983 SNP (4,309 PD patients, 4,287 controls), and six studies for the rs4919621 SNP (2,724 PD patients, 2,285 controls), and the risk for PD, global diagnostic odds ratios (95% confidence intervals) for rs3758549, rs2281983, and rs4919621 were, respectively, 1.00 (0.89-1.12) (p = 0.979), 0.99 (0.91-1.09) (p = 0.896), and 0.98 (0.83-1.16) (p = 0.844) for the total group. The separate analysis in Caucasian and Chinese subjects on the frequency of the minor allele of the three SNPs analyzed did not show significant differences between PD patients and controls in both subgroups. rs2281983 and rs4919621 SNPs were related with early-onset PD risk in Caucasians. Conclusion: The results of the meta-analysis suggest that rs3758549, rs2281983, and rs4919621 SNPs are not major determinants of the risk for PD.

Differential Synaptic Remodeling by Dopamine in Direct and Indirect Striatal Projection Neurons in Pitx3−/−Mice, a Genetic Model of Parkinson's Disease

“…In this line, our results show that the lack of dopamine reduces spine density similarly in dSPNs and iSPNs, demonstrating that both D 1 and D 2 receptors are necessary for spine formation and maintenance. These results are in agreement with our previous results showing that the lack of dopamine in PD reduces spine density in both types of SPNs (Suárez et al, 2014(Suárez et al, , 2016Gagnon et al, 2017). In addition, spine loss occurred mainly in the predominant types of spines, mushroom and thin, which is in agreement with our findings in the 6-OHDA mice model (Suarez et al, 2016).…”

“…Our experimental model does not allow us to determine whether the requirement for dopamine for normal spine density occurs during development, in adulthood, or both. However, previous studies using organotypic corticostriatal cocultures have shown that dopamine is essential both for spine formation during development and for spine maintenance in mature SPNs (Deutch, 2006;Deutch et al, 2007;Neely et al, 2007;Garcia et al, 2010;Tian et al, 2010), and that both are D 1 and D 2 receptor dependent (Fasano et al, 2013). In this line, our results show that the lack of dopamine reduces spine density similarly in dSPNs and iSPNs, demonstrating that both D 1 and D 2 receptors are necessary for spine formation and maintenance.…”

“…In slices from sham-operated WT mice, the doses of L-DOPA used to activate D 1 receptor did not affect SPN excitability (Calabresi et al, 1993b;Suárez et al, 2014), suggesting that the hyperexcitability we observe in the Pitx3 Ϫ/Ϫ mice is an abnormal response of SPNs that have never received dopaminergic afferents, which is further enhanced in dyskinesia. This striatal hypersensitivity to D 1 receptor stimulation may mediate the widespread molecular and electrophysiological changes observed in dyskinetic animals and patients (Boraud et al, 2001;Guigoni et al, 2005;Halje et al, 2012;Trusel et al, 2015;Araque et al, 2017). Together, these results indicate that in BAC-Pitx3 Ϫ/Ϫ dyskinetic mice there is a functional imbalance in the striatal projection neurons, as follows: the dSPNs have an increased firing rate and the D 1 receptor is sensitized, whereas the D 2 receptor is desensitized in iSPNs.…”

“…While SPNs receive glutamatergic and dopaminergic inputs on the same spines (Silberberg and Bolam, 2015), the localization of the dopaminergic inputs on the neck of the spines gives dopamine a central role in regulating spine function (Bolam et al, 2000;Deutch et al, 2007). Dopamine facilitates spine formation on SPNs via D 1 and D 2 receptors (Fasano et al, 2013), and the loss of striatal dopamine in Parkinson's disease (PD) reduces the dendritic length and spine density to a similar extent in both types of SPNs (Solís et al, 2007;Fieblinger et al, 2014;Suarez et al, 2014Suarez et al, , 2016Gagnon et al, 2017). Curiously, this spine loss produces opposite changes in synaptic transmission, facilitating synaptic strength in dSPNs and reducing it in iSPNs (Suarez et al, 2016).…”

Developmental Dieldrin Exposure Alters DNA Methylation at Genes Related to Dopaminergic Neuron Development and Parkinson’s Disease in Mouse Midbrain

“…Pitx3 encodes the pituitary homeobox 3 protein, a transcription factor that shows restricted, constitutive expression in the midbrain, where it is thought to play a role in development and maintenance of dopaminergic neurons (Li et al, 2009). Although some studies have shown associations between human PITX3 polymorphisms and PD (Fuchs et al, 2009;Bergman et al, 2010;Haubenberger et al, 2011), findings have been inconsistent, and a recent meta-analysis suggested that the identified polymorphisms do not show significant associations with risk of PD (Jiménez-Jiménez et al, 2014). Reflecting this uncertainty, unlike the Nr4a2 and Lmx1b genes, we did not identify dieldrin-related differential methylation at the Pitx3 gene ( Figure 5C).…”