Mechanisms of compensation for loss of brain dopamine

项目总结/摘要 有很大的兴趣，在补偿机制，可能会发挥作用，延迟 帕金森病的早期/症状前期症状发作。这里我们使用 多巴胺（DA）缺乏的果蝇和小鼠模型，以表征代偿性 可能与人类状况有关的机制。在过去的一段时间里，我们 部分定位了一个负责“多巴胺旁路”表型的遗传元件， 称为“DD-Hi”，其中“DD”是指多巴胺缺乏。DD-Hi苍蝇显示接近正常 尽管大脑多巴胺（DA）完全缺乏，但与低水平的运动活动相比， 自发活动DA缺乏系，DD-Lo。为即将到来的赠款期提出的工作 将致力于更精确地绘制这种特征的遗传图谱。相关目标将有助于实现这一目标 努力，识别和表征在DA神经元中起作用的共递质， 缺乏多巴胺，并分析单个DA神经元的转录组。我们将追求一个 在小鼠中的平行模型中，使小鼠在特定的大脑区域缺乏多巴胺， 为多巴胺依赖性自动调节回路提供了证据， DA神经元发育和维持所需的一组基因的表达， 特别是在SNc（黑质部）中。鉴于SNc DA的高敏感性 早期帕金森病的神经元，这种调节回路的确认可能既有 临床和基础科学的影响。我们的希望是，在苍蝇和 小鼠将有助于鉴定保守基因和机制， 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.