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The role of transcription factor Pitx3 in dopamine neuron development and Parkinson's disease.

ABSTRACT: Parkinson's disease (PD) is characterized by the selective loss of dopamine (DA) neurons in the substantia nigra compacta (SNc). The transcription factor Pitx3 is important for the differentiation and maintenance of midbrain DA neurons during development. There is highly restricted and constitutive expression of Pitx3 in the SNc and ventral tegmental area (VTA) of the midbrain after birth. In addition to its importance during development, Pitx3 also has roles in the long-term survival and maintenance of the midbrain DA neurons. In this review, we discuss the function of Pitx3 throughout the life of midbrain neurons and the contribution of Pitx3 to disease mechanisms.

SUBMITTER: Li J

PROVIDER: S-EPMC2872921 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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The role of transcription factor Pitx3 in dopamine neuron development and Parkinson's disease.

Li Jia J Dani John A JA Le Weidong W

Current topics in medicinal chemistry 20090101 10

Parkinson's disease (PD) is characterized by the selective loss of dopamine (DA) neurons in the substantia nigra compacta (SNc). The transcription factor Pitx3 is important for the differentiation and maintenance of midbrain DA neurons during development. There is highly restricted and constitutive expression of Pitx3 in the SNc and ventral tegmental area (VTA) of the midbrain after birth. In addition to its importance during development, Pitx3 also has roles in the long-term survival and mainte ...[more]

PMID: 19754401

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Project description:: Accumulative evidence indicated that the pathologically accumulated metal ions (iron species and Mn3+) and abnormally up-regulated monoamine oxidase B (MAOB) activity induced oxidation of endogenous dopamine (DA) can lead to mitochondria impairment, lysosome dysfunction, proteasome inhibition, and selective DA neuron vulnerability, which is implicated in the pathogenesis of Parkinson's disease (PD). The DA oxidation can generate deleterious reactive oxygen species (ROS) and highly reactive DA quinones (DAQ) to induce DA-related toxicity, which can be alleviated by DA oxidation suppressors, ROS scavengers, DAQ quenchers, and MAOB inhibitors. On the other hand, the nuclear factor erythroid 2-related factor 2 (Nrf2)-Keap1 and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1?) anti-oxidative and proliferative signaling pathways play roles in anti-oxidative cell defense and mitochondria biogenesis, which is implicated in DA neuron protections. Therefore, agents with capabilities to suppress DA-related toxicity including inhibition of DA oxidation, scavenge of ROS, detoxification of DAQ, inhibition of MAOB, and modulations of anti-oxidative signaling pathways can be protective to DA neurons. Accumulative evidence shows that tea or coffee consumptions and smoking are related to deceased PD prevalence with unknown mechanisms. In this study, we investigate the protective capabilities of tea polyphenols and other PD relevant agents to inhibit DA-related toxicity and protect against environmental or genetic factors induced DA neuron degeneration in vitro and in vivo. We find that tea polyphenols can significantly suppress DA-related toxicity to protect DA neurons. The tea polyphenols can protect DA neurons via inhibition of DA oxidation, conjugation with DAQ, scavenge of ROS, inhibition of MAOB, and modulations of Nrf2-Keap1 and PGC-1? anti-oxidative signaling pathways. The tea polyphenols with more phenolic hydroxyl groups and ring structures have stronger protective functions. The protective capabilities of tea polyphenols is further strengthened by evidence that phenolic hydroxyl groups can directly conjugate with DAQ. However, GSH and other sulfhydyl groups containing agents have weaker capabilities to abrogate DA oxidation, detoxify ROS and DAQ and inhibit MAOB; whereas nicotine (NICO) and caffeine (CAF) can only modulate Nrf2-Keap1 and PGC-1? pathways to protect DA neurons weakly. The tea polyphenols are identified to protect against overexpression of mutant A30P ?-synuclein (?-syn) induced DA neuron degeneration and PD-like symptoms in transgenic Drosophila. Based on achievements from current studies, the excellent and versatile protective capabilities of tea polyphenols are highlighted, which will contribute and benefit to future anti-PD therapy.

Dataset Information

The role of transcription factor Pitx3 in dopamine neuron development and Parkinson's disease.

Publications

The role of transcription factor Pitx3 in dopamine neuron development and Parkinson's disease.

Similar Datasets

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