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Midbrain dopamine (DA) neurons are involved in cognition, control of motor activity, and emotion-related behaviors. Degeneration of DA neurons particularly in the substantia nigra is a hallmark of Parkinson's disease. The homeobox transcription factor, Pitx3, plays a critical role in the development, function, and maintenance of midbrain DA neurons. We found that in young adult Pitx3-null mice, Pitx3(−/−), there was decreased tyrosine hydroxylase staining, indicating a loss of DA neurons particularly in the substantia nigra. In addition, fast-scan cyclic voltammetry and microdialysis assays of DA release indicated that the lack of Pitx3 caused a significant reduction of striatal DA release. Tonic DA release was impaired more significantly than the phasic DA release induced by burst firing of DA neurons. Furthermore, behavioral tests revealed that Pitx3(−/−) mice displayed abnormal motor activities, including impaired motor coordination and decreased locomotion. In summary, these data provide further evidence that Pitx3 is specifically required for DA-related function and, if impaired, Pitx3 could contribute during the pathogenesis of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Abstract: Most cases of Alzheimer''s disease (AD) arise through interactions between genetic and environmental factors. It is believed that hypoxia is an important environmental factor influencing the development of AD. Our group has previously demonstrated that hypoxia increased β-amyloid (Aβ) generation in aged AD mice. Here, we further investigate the pathological role of prenatal hypoxia in AD. We exposed the pregnant APPSwe/PS1A246E transgenic mice to high-altitude hypoxia in a hypobaric chamber during days 7–20 of gestation. We found that prenatal hypoxic mice exhibited a remarkable deficit in spatial learning and memory and a significant decrease in synapses. We also documented a significantly higher level of amyloid precursor protein, lower level of the Aβ-degrading enzyme neprilysin, and increased Aβ accumulation in the brain of prenatal hypoxic mice. Finally, we demonstrated striking neuropathologic changes in prenatal hypoxic AD mice, showing increased phosphorylation of tau, decreased hypoxia-induced factor, and enhanced activation of astrocytes and microglia. These data suggest that although the characteristic features of AD appear later in life, hypoxemia in the prenatal stage may contribute to the pathogenesis of the disease, supporting the notion that environmental factors can trigger or aggravate AD. [Copyright &y& Elsevier]

Abstract: The nuclear receptor related 1 (Nurr1) transcription factor contributes to the development and maintenance of dopamine (DA) neurons in the brain. We found that heterozygous Nurr1 knockout (Nurr1 +/−) influenced the age-dependent decline in the number of DA neurons and influenced DA signaling. We examined the DA marker, tyrosine hydroxylase, using immunohistochemistry, and we measured DA signaling using fast-scan cyclic voltammetry in 3 age groups of wild-type (Nurr1 +/+) and mutant (Nurr1 +/−) mice: 3–6, 9–12, and 15–23 mo old. Prior to significant loss of DA neurons and to the onset of parkinsonian symptoms, young Nurr1 +/− mice (3–6 mo) exhibited a decrease in peak evoked DA release that was partially countered by a decrease in the rate of DA reuptake. As peak evoked DA release declined with age for both the wild-type and Nurr1 +/− mice, both genotypes manifested decreased DA reuptake. As the DA release fell further with age, decreased DA reuptake eventually could not adequately compensate the Nurr1 +/− mice. The results indicated that Nurr1 deficiency led to impaired DA release even before significant DA neuron loss. [Copyright &y& Elsevier]

Abstract: PITX3 is a transcription factor important for the differentiation and survival of midbrain dopaminergic neurons during the development. Recent reports suggest that single nucleotide polymorphisms (SNP) in the gene may be associated with Parkinson''s disease (PD). To verify their findings and to determine the nature of the association in a subset of our PD patients we have analyzed two PITX3 SNPs (rs2281983 and rs4919621) in 265 PD patients and compared them with 210 age-matched healthy controls. Our data show that the substitutions of C/T in SNP1 and A/T in SNP2 are significantly higher in PD, and this finding is even more robust in young onset and familial PD as compared with age-matched healthy controls. Our findings indicate that PITX3 may play a role in the pathogenesis of PD. [Copyright &y& Elsevier]