Mechanisms of compensation for loss of brain dopamine

项目摘要/摘要 人们对可能起到延迟作用的补偿机制非常感兴趣 帕金森氏病早期/症状前期症状的出现。在这里我们使用 果蝇和小鼠多巴胺缺乏模型的代偿性研究 可能与人类状况相关的机制。在之前的授权期内，我们 部分定位了导致多巴胺旁路表型的遗传因素，此后 被称为‘DD-Hi’，其中‘DD’指的是多巴胺缺乏。DD-Hi苍蝇接近正常 尽管完全缺乏脑多巴胺(DA)，但运动活动水平与低水平相比 运动活动DA缺陷系，DD-LO。为即将到来的赠款期间拟议的工作 将致力于更精确地绘制这种特征的基因图谱。相关的目标将有助于实现这一点 努力，识别和表征在多巴胺神经元中起作用的共递质 缺乏多巴胺，并分析单个DA神经元的转录本。我们将推行一项 小鼠的平行模型，使小鼠在特定脑区出现多巴胺缺陷 为多巴胺依赖的自动调节环路提供证据，从而导致持续 DA神经元发育和维持所需的一组基因的表达， 尤其是黑质致密部(SNC)。鉴于SNC DA的高度敏感性 早期帕金森氏病中的神经元，证实这一调节电路可能两者都有 临床和基础科学方面的影响。我们希望在苍蝇身上寻找类似的模型，并 小鼠将有助于识别保守的基因和机制，从而为治疗提供信息 人类的目标和策略。

Project Summary/Abstract There is great interest in the compensatory mechanisms that may function to delay onset of symptoms in the early/presymptomatic phase of Parkinson’s Disease. Here we use Drosophila and mouse models of dopamine (DA) deficiency to characterize compensatory mechanisms that may be relevant to the human condition. In the previous grant period, we partly localized a genetic element responsible for the ‘Dopamine Bypass’ phenotype, hereafter referred to as ‘DD-Hi’, where ‘DD’ refers to Dopamine Deficient. DD-Hi flies show near normal levels of locomotor activity despite total deficiency of brain dopamine (DA), compared to the low locomotor activity DA deficient line, DD-Lo. The work proposed for the upcoming grant period will work toward more precise genetic mapping of this trait. Related aims will contribute to this effort, identifying and characterizing a co-transmitter that functions in DA neurons that are devoid of dopamine, and analyzing the transcriptomes of single DA neurons. We will pursue a parallel model in mice, where mice that are made dopamine deficient in specific brain regions provide evidence for a dopamine dependent autoregulatory loop that leads to continued expression of a set of genes required for development and maintenance of DA neurons, particularly in the SNc (substantia nigra pars compacta). Given the high susceptibility of SNc DA neurons in early Parkinsons Disease, confirmation of this regulatory circuit could have both clinical and basic science implications. Our hope is that pursuing analogous models in flies and mice will aid in identification of conserved genes and mechanisms that will inform therapeutic targets and strategies in humans.