GATA2 as a therapeutic target in Parkinson's disease

描述(申请人提供)：帕金森病(PD)与黑质(SN)中铁和1-突触核蛋白(1-syn)的病理性增加有关，这些特征是使用杀虫剂鱼藤酮复制的PD动物模型。1-羟色胺和铁都在黑质多巴胺神经元中蓄积，并具有细胞毒性；然而，它们病理性蓄积的机制尚不清楚。我们确认了转铁蛋白/转铁蛋白受体2(TfR2)介导的黑质多巴胺神经元铁蓄积的机制，并发现TfR2在鱼藤酮大鼠的多巴胺神经元中水平增加。GATA转录因子在体外对1-syn的表达具有正向调节作用，其在造血中的作用已被充分研究。异构体GATA2在人黑质中表达，初步研究已将GATA2定位于大鼠黑质中的多巴胺神经元。初步数据表明，GATA2在体外正向调节TfR2的转录。因此，GATA2可能在体内对黑质多巴胺神经元中的1-syn和TfR2起正向和协同调节作用，治疗性抑制GATA2可能同时减轻1-syn和铁对帕金森病的有害影响。本建议将利用病毒介导的大鼠黑质黑质体内基因沉默来检验下列假设：1)GATA2调节大鼠黑质多巴胺神经元中的1-syn和TfR2；2)抑制黑质多巴胺神经元中的GATA2导致鱼藤酮处理后1-syn和铁的积累减少，从而减轻黑质纹状体的变性。这项工作将研究如何通过抑制转录因子GATA2，使用体内病毒介导的基因沉默来协调减弱帕金森病的两个明显不同的病理特征-1-突触核蛋白的积累和黑质多巴胺神经元中铁的积累。这些目标的成功实现将使GATA2成为一个潜在的治疗靶点，可以利用基因疗法来改善与1-syn和人类帕金森病铁积累相关的细胞毒性。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is associated with pathological increases in iron and 1-synuclein (1-syn) in the substantia nigra (SN), and these features are reproduced animal models of PD that use the pesticide rotenone. Both 1-syn and iron accumulate in nigral dopamine neurons and are cytotoxic; however, the mechanism underlying their pathological accumulation is unknown. We have identified a transferrin/transferrin receptor 2 (TfR2)-mediated mechanism for iron accumulation in nigral dopamine neurons, and have found that TfR2 levels are increased in dopamine neurons in the rotenone rat. GATA transcription factors, whose role has been well characterized in hematopoiesis, have recently been shown to positively regulate the expression of 1-syn in vitro. The isoform GATA2 is expressed in human SN, and preliminary studies have localized GATA2 to dopamine neurons in rat SN. Preliminary data indicate that GATA2 positively regulates TfR2 transcription in vitro. Thus it is possible that GATA2 positively and coordinately regulates both 1-syn and TfR2 in nigral dopamine neurons in vivo, and that therapeutic GATA2 inhibition may simultaneously ameliorate the deleterious effects of both 1-syn and iron in PD. This proposal will use in vivo viral-mediated gene silencing in rat SN to test the following hypotheses: 1) GATA2 regulates 1-syn and TfR2 in rat nigral dopamine neurons, and 2) inhibition of GATA2 in nigral dopamine neurons leads to decreased accumulation of 1-syn and iron following rotenone treatment, thereby attenuating nigrostriatal degeneration. This work will examine how two apparently disparate pathological features of PD-the accumulation of 1-synuclein and the accumulation of iron within nigral dopamine neurons-may be coordinately attenuated via inhibition of the transcription factor, GATA2, using in vivo viral-mediated gene silencing. Successful completion of these aims would establish GATA2 as a potential therapeutic target that could be exploited using gene therapy to ameliorate the cellular toxicity associated with both 1-syn and iron accumulation in human PD.