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

虽然帕金森病（PD）患者有许多治疗选择，但这些治疗方法 并不是对所有患者都有效。事实上，最近对ELLDOPA研究的回顾性分析 报告称，接受等效左旋多巴剂量的早期PD受试者经历了 根据联合帕金森氏症评估，反应范围从100%改善到242%恶化 疾病评定量表第三部分（ADRRS-III，运动分项评分）。这个例子强调了令人难以置信的 对标准治疗抗帕金森病治疗的临床反应的异质性，即使疾病严重程度 考虑了在过去的几十年里， 神经移植的再生方法。虽然一些PD患者表现出明显和持久的益处， 在移植原代多巴胺（DA）神经元后，许多神经元也没有显示出或显示出有限的益处。最近 老年帕金森病大鼠的临床前数据以及来自两个里程碑临床报告的数据提供 令人信服和清醒的数据表明，即使移植的DA神经元和 实现了广泛的神经突生长，仍然存在干扰功能回路恢复的障碍 在老年帕金森病患者的大脑中。随着临床移植试验的重新出现， 风险因素对DA末端重塑的临床反应性产生负面影响。试图解构 PD的复杂性和对治疗的反应，我们最近确定了一个候选遗传变异， 在人群中高达40%的患病率，这可能在这方面证明是有用的;具体而言， 脑源性神经营养因子基因功能性单核苷酸多态性rs6265 （BDNF），导致BDNF释放功能障碍。我们最近观察到治疗效果下降 口服左旋多巴在两个不同的队列的PD患者与这个SNP风险等位基因。在当前应用中， 我建议检验这一假设，即这种危险等位基因也是对DA神经元的临床反应的变异性的基础 腹膜透析患者的移植具体地说，我们假设BDNF是一个未被认识到的贡献者， 在一项研究中报告了移植的DA神经元大量存活和缺乏行为功效的不一致发现， PD患者的亚群，并与帕金森病大鼠的正常衰老相关。在本申请中，我们 我提出了三个具体的目标来测试总体假设，即受损的BDNF信号传导，无论是通过 这种常见的SNP和/或高龄是限制功能性DA末端重塑的关键因素。朝向 为此，我们已经产生了人rs6265 BDNF变异体的敲入大鼠模型，并建议使用该模型。 一种新的工具来表征其对功能和突触的影响以及与衰老和DA耗竭的相互作用， 整合新的DA终端在帕金森病纹状体使用神经移植作为一个模型系统。

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.