Impact of Dysfunctional BDNF on Dopamine Terminal Remodeling in the Parkinsonian Striatum

虽然帕金森氏病(PD)患者有许多治疗选择，但这些治疗方法 并不是所有患者的效果都一样好。事实上，最近对ELLDOPA研究的回顾分析 报道称，接受等量左旋多巴治疗的早期帕金森病患者经历了 根据联合帕金森氏症评估，反应从100%的改善到242%的恶化 疾病评定量表第三部分(UPDRS-III，运动亚分)。这个例子强调了不可思议的 标准护理抗帕金森病治疗的临床反应的异质性，即使疾病严重程度是 考虑到这一点。在过去的几十年里，也有类似的实验结果被报道。 神经移植的再生法。虽然一些帕金森病患者表现出显著和持久的好处 在植入初级多巴胺(DA)神经元后，许多神经元也显示出没有或有限的益处。近期 老年帕金森病大鼠的临床前数据以及两个里程碑式的临床报告提供了 令人信服和发人深省的数据表明，即使移植的DA神经元和 广泛的轴突生长达到，干扰功能电路恢复的障碍(S)仍然存在 在老年人中，帕金森症患者的大脑。随着临床移植试验的重新出现，目前还不确定具体是什么 危险因素对DA终末重塑的临床反应有负面影响。在试图解构 帕金森病的复杂性和对治疗的反应，我们最近发现了一个候选基因变异，与 在人口中的流行率高达40%，这在这方面可能被证明是有用的；具体地说， 脑源性神经营养因子BDNF基因功能单核苷酸多态性rs6265 (BDNF)，导致BDNF释放功能障碍。我们最近观察到治疗效果减弱。 口服左旋多巴在两个不同的PD患者队列中具有该SNP风险等位基因。在当前的应用程序中，我们 建议检验这一假设，即该风险等位基因也是多巴胺神经元临床反应变异性的基础 帕金森病患者的移植治疗。具体地说，我们假设BDNF是未被承认的贡献者 关于移植的DA神经元的大量存活和缺乏行为疗效的不一致的发现报告在一个 帕金森病大鼠帕金森病患者亚群及其与正常衰老的关系。在此应用程序中，我们 提出三个具体的目标来测试主要的假设，即通过以下方式损害BDNF信号 这种常见的SNP和/或高龄是限制功能性DA终末重塑的关键因素。冲向 为此，我们已经建立了人类rs6265 bdnf变异体的敲入大鼠模型，并建议使用 一种新的工具来表征其对功能和突触的影响及其与衰老和DA耗竭的相互作用 以神经移植为模型系统整合帕金森病患者纹状体内新的DA终末。

While there are a number of therapeutic options for individuals with Parkinson's disease (PD) these therapies do not work uniformly well in all patients. Indeed, a recent retrospective analysis of the ELLDOPA study reported that early-stage PD subjects receiving equivalent levodopa doses experienced a magnitude of response ranging from a 100% improvement to a 242% worsening as assessed with the United Parkinson's Disease Rating Scale part III (UPDRS-III, motor subscore). This example underscores the incredible heterogeneity in clinical response to standard-of-care anti-parkinsonian therapy, even when disease severity is taken into account. Similar findings have been reported over the past several decades for the experimental regenerative approach of neural grafting. While some PD patients have shown marked and lasting benefit following engraftment of primary dopamine (DA) neurons, many have also shown no or limited benefit. Recent preclinical data in aged parkinsonian rats together with that from two milestone clinical reports provide compelling and sobering data demonstrating that even when robust survival of grafted DA neurons and extensive neurite outgrowth is achieved, obstacle(s) remain that interfere with functional circuit restoration within the aged, parkinsonian brain. As clinical grafting trials are reemerging, it remains uncertain what specific risk factors negatively impact clinical responsiveness to DA terminal remodeling. In attempt to deconstructing the complexity of PD and response to therapy, we recently identified one candidate genetic variant, with prevalence of up to 40% in the human population, which may prove useful in this regard; specifically, a functional single nucleotide polymorphism (SNP) rs6265 in the Bdnf gene for brain-derived neurotrophic factor (BDNF) that results in dysfunctional BDNF release. We have recently observed diminished therapeutic efficacy of oral levodopa in two distinct cohorts of PD patients with this SNP risk allele. In the current application we propose to test the hypothesis that this risk allele also underlies the variability in clinical response to DA neuron grafting in PD patients. Specifically, we hypothesize that BDNF is an unrecognized contributor to the discordant finding of abundant survival of grafted DA neurons and lack of behavioral efficacy reported in a subpopulation of PD patients and in association with normal aging in parkinsonian rats. In this application we propose three Specific Aims to test the overarching hypothesis that impaired BDNF signaling, either through this common SNP and/or advanced age, is a key factor in limiting functional DA terminal remodeling. Toward this end, we have generated a knock-in rat model of the human rs6265 BDNF variant and propose to use this novel tool to characterize its effects and interaction with aging and DA-depletion on the function and synaptic integration of new DA terminals in the parkinsonian striatum using neural grafting as a model system.