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

功能失调的 BDNF 对帕金森纹状体多巴胺末端重塑的影响

• 批准号: 10547752
• 负责人: KATHY Steece STEECE-COLLIER
• 金额: $ 32.46万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547752
• 关键词: Age; Aging; Alleles; BDNF gene; Behavioral; Biological Models; Brain; Brain-Derived Neurotrophic Factor; Cells; Clinical; Clinical Trials; Clinical Trials Design; Consensus; Corpus striatum structure; Data; Dendritic Spines; Disease Progression; Dopamine; Dose; Elderly; Embryo; Engraftment; Future; Genes; Genetic Polymorphism; Graft Survival; Heterogeneity; Human; Impairment; Individual; Inferior; Knock-in; Length; Levodopa; Medical; Messenger RNA; Microdialysis; Modeling; Motor; Movement Disorder Society Unified Parkinson' s Disease Rating Scale; Nature; Neurites; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Oral; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Persons; Play; Population; Preclinical Testing; Prevalence; Rattus; Reporting; Research; Risk Factors; Role; Severity of illness; Signal Transduction; Single Nucleotide Polymorphism; Stress; Supplementation; Synapses; Testing; Therapeutic; Transplantation; Treatment Efficacy; Uncertainty; Up-Regulation; Variant; aged; aging brain; brain dysfunction; cohort; density; dopamine graft; dopaminergic neuron; experience; genetic risk factor; genetic variant; improved; in vivo; interest; neural graft; normal aging; novel; parkinsonian rodent; pre-clinical; regenerative; regenerative approach; release factor; response; restoration; risk variant; side effect; sobriety; standard of care; synaptogenesis; tool; transcription factor; treatment response; trial planning

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.

虽然帕金森病 (PD) 患者有多种治疗选择，但这些疗法 并非对所有患者都有效。事实上，最近对 ELLDOPA 研究的回顾性分析 报道称，接受同等左旋多巴剂量的早期 PD 受试者经历了严重的 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（UPDRS-III，运动分项评分）。这个例子强调了令人难以置信的 即使疾病严重程度不同，标准护理抗帕金森病治疗的临床反应也存在异质性 考虑到。在过去的几十年里，类似的实验结果也被报道过。 神经移植的再生方法。虽然一些帕金森病患者已显示出显着且持久的益处 在原代多巴胺（DA）神经元植入后，许多神经元也没有显示出任何益处或效果有限。最近的 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了 令人信服且发人深省的数据表明，即使移植的 DA 神经元和 实现了广泛的神经突生长，仍然存在干扰功能电路恢复的障碍 在老年的帕金森病大脑中。随着临床移植试验重新出现，目前仍不确定具体是什么 危险因素对 DA 末端重塑的临床反应产生负面影响。试图解构 鉴于帕金森病的复杂性和对治疗的反应，我们最近确定了一种候选遗传变异， 人群中的患病率高达 40%，这在这方面可能是有用的；具体来说，一个 脑源性神经营养因子 Bdnf 基因中的功能性单核苷酸多态性 (SNP) rs6265 (BDNF) 导致 BDNF 释放功能失调。我们最近观察到治疗效果下降 两组不同的携带该 SNP 风险等位基因的 PD 患者口服左旋多巴的效果。在当前的应用程序中我们 提议检验以下假设：该风险等位基因也是 DA 神经元临床反应变异性的基础 PD患者进行移植。具体来说，我们假设 BDNF 是一个未被认识到的贡献者 移植的 DA 神经元的大量存活和缺乏行为功效的不一致发现 PD 患者亚群及其与帕金森病大鼠正常衰老的关系。在这个应用程序中我们 提出三个具体目标来测试损害 BDNF 信号传导的总体假设，或者通过 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。走向 为此，我们生成了人类 rs6265 BDNF 变体的敲入大鼠模型，并建议使用该模型 表征其与衰老和 DA 消耗对功能和突触的影响和相互作用的新工具 使用神经移植作为模型系统将新的 DA 终端整合到帕金森病纹状体中。

项目成果

Repairing the Aged Parkinsonian Striatum: Lessons from the Lab and Clinic.

修复老年帕金森纹状体：实验室和临床的经验教训。

• DOI: 10.4172/2155-9899.1000476
• 发表时间: 2016
• 期刊: Journal of clinical & cellular immunology
• 作者: Mercado,NatoshaM;Collier,TimothyJ;Freeman,Thomas;Steece-Collier,Kathy
• 通讯作者: Steece-Collier,Kathy

The BDNF Val66Met polymorphism (rs6265) enhances dopamine neuron graft efficacy and side-effect liability in rs6265 knock-in rats.

BDNF Val66Met 多态性 (rs6265) 增强 rs6265 敲入大鼠中的多巴胺神经元移植功效和副作用倾向。

• DOI: 10.1016/j.nbd.2020.105175
• 发表时间: 2021-01
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Mercado NM;Stancati JA;Sortwell CE;Mueller RL;Boezwinkle SA;Duffy MF;Fischer DL;Sandoval IM;Manfredsson FP;Collier TJ;Steece-Collier K
• 通讯作者: Steece-Collier K

New Frontiers in Neurodegeneration and Regeneration Associated with Brain-Derived Neurotrophic Factor and the rs6265 Single Nucleotide Polymorphism.

• DOI: 10.3390/ijms23148011
• 发表时间: 2022-07-20
• 期刊: International journal of molecular sciences
• 影响因子: 5.6