Interneurons as Early Drivers of Huntington´s Disease Progression

中间神经元是亨廷顿病进展的早期驱动因素

基本信息

批准号：
10672973
负责人：
Mark F Mehler
金额：
$ 69.9万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672973
关键词：
Ablation Address Adult Affect Age Allografting Animal Model Autopsy Behavioral Brain Brain region Cell Transplantation Cells Cerebral cortex Characteristics Clinical Code Complement Corpus striatum structure Coupling DNA Damage Data Development Developmental Process Disease Disease Progression Disease model Effectiveness of Interventions Embryo Event Exons Exposure to Foundations Functional disorder Genes Genetic Genetic Diseases Genetic Polymorphism Goals Human Huntington Disease Huntington gene Impairment Interneurons Intervention Knowledge Laboratories Laboratory Study Late-Onset Disorder Lead Length Life Ligands Link Literature Mediating Mission Motor Mus Neonatal Neurodegenerative Disorders New York Nucleotides Onset of illness Outcome Output Pathogenesis Pathogenicity Pathologic Pathology Phase Predictive Value Prevention Public Health Reporting Research Role Specimen Stress Supplementation System Testing Therapeutic Therapeutic Intervention Time Transplantation Trinucleotide Repeat Expansion Trinucleotide Repeats United States National Institutes of Health Universities age related cell type critical developmental period critical period developmental disease developmental plasticity effectiveness evaluation excitotoxicity experimental study gamma-Aminobutyric Acid genetic approach innovation insight intervention effect motor deficit motor disorder motor impairment mouse model mutant neural network neurogenesis neuroimaging neuropathology novel postnatal postnatal period preclinical study prevent pup receptor regenerative approach response restoration stem cells targeted treatment therapeutically effective trait white matter

项目摘要

Huntington’s disease (HD) is an insidious neurodegenerative disorder caused by trinucleotide repeat expansion in exon 1 of the gene that codes for Huntingtin (mHtt). The pathogenic mechanisms underlying HD remain poorly understood. Studies of HD models have documented numerous developmental impairments during ‘pre- manifest’ HD. Using conditional HD models, the Mehler laboratory team has previously shown that such developmental processes mediate disease pathogenesis. Now, this team provides evidence demonstrating that interneuron neurogenesis is prominently disrupted in mouse models of HD, leading to deficits in the complement of these interneurons within the developing cerebral cortex. Such deficits are of great importance, as studies have shown these lead to permanent changes in cortico-striatal connectivity laying the foundation for cortical hyperexcitability, impaired excitation-inhibition coupling, and striatal excitotoxic stress later in life. Although cortical interneuron deficits have previously been reported in HD cases, their role in HD pathogenesis has never been further interrogated. This application tests the central hypothesis that HD is caused by impairments in the developmental elaboration of selective cortical interneuron subtypes; therefore, prevention of the adverse developmental effects of these interneuron deficits will ameliorate or even prevent disease occurrence. This hypothesis is further supported by preliminary data showing that genetic rescue of developing interneurons precludes the onset of characteristic features of HD in BACHD mice: motor coordination deficits, hypomyelination of subcortical white matter tracts and striatal degeneration. Specific Aim 1 (SA1) initially defines whether interneuron progenitor cell supplementation via heterochronic grafts into mutant neonatal pups favorably modifies the occurrence of motor deficits and striatal degeneration, two distinctive traits of HD. This aim also examines whether the role of interneurons in disease progression takes place at the expense of quantitative deficits or through additional factors associated with expression of mutant huntingtin in these cells. SA2 interrogates the interneuron-dependent pathogenic mechanisms mediating HD, focusing on putative modulatory effects of GABA, Reelin and complementary ligand release. Finally, SA3 employs a large array of HD postmortem specimens from two major brain banks to define the role in disease progression of cortical interneuron deficits. This aim also interrogates whether known HD genetic modifiers, including trinucleotide expansion length and/or polymorphisms of DNA damage response genes modulate the extent of interneuron alterations, as well as whether these cells mediate the predictive effects of these genetic modifiers on age at disease onset/progression. Overall, confirmation of the central hypothesis would have substantial implications for the field, as it will provide strong evidence regarding the intersectional roles of interneurons in HD pathogenesis and also define a novel early-stage therapeutic window for preventing HD onset and progression for a neurodegenerative disorder currently lacking substantive and effective therapeutic interventions.

亨廷顿病 (HD) 是一种由三核苷酸重复扩增引起的隐匿性神经退行性疾病编码亨廷顿蛋白 (mHtt) 的基因的外显子 1 中 HD 的致病机制仍然很差。对 HD 模型的研究已经记录了“前期”期间的许多发育障碍。 Mehler 实验室团队之前已经使用条件 HD 模型证明了这一点。现在，该团队提供的证据证明发育过程介导疾病发病机制。在 HD 小鼠模型中，中间神经元的神经发生受到显着破坏，导致补体缺陷研究表明，这些中间神经元在发育中的大脑皮层中的缺陷非常重要。已经表明这些会导致皮质纹状体连接的永久性变化，为皮质纹状体的连接奠定基础过度兴奋、兴奋-抑制耦合受损以及晚年纹状体兴奋毒性应激。皮质间神经元缺陷以前曾在 HD 病例中报道过，但其在 HD 发病机制中的作用从未有过报道。该应用程序测试了 HD 是由损伤引起的中心假设。选择性皮质中间神经元亚型的发育阐述，因此，预防不良反应；这些中间神经元缺陷的发育影响将改善甚至预防疾病的发生。初步数据进一步支持了这一假设，这些数据表明发育中的中间神经元的基因拯救阻止 BACHD 小鼠 HD 特征性症状的发生：运动协调缺陷、髓鞘形成不足皮层下白质束和纹状体变性的初步定义是否。通过异时移植到突变新生幼崽中有利地补充中间神经元祖细胞改变运动缺陷和纹状体变性的发生，这是 HD 的两个显着特征。检查中间神经元在疾病进展中的作用是否以定量分析为代价缺陷或通过与这些细胞中突变亨廷顿蛋白表达相关的其他因素。探讨介导 HD 的中间神经元依赖性致病机制，重点关注假定的调节 GABA、Reelin 和互补配体释放的影响最后，SA3 采用了大量的 HD。来自两个主要脑库的尸检标本以确定皮质在疾病进展中的作用该目标还询问是否存在已知的 HD 遗传修饰因子，包括三核苷酸。 DNA损伤反应基因的扩增长度和/或多态性调节中间神经元的范围改变，以及这些细胞是否介导这些遗传修饰物对年龄的预测作用总体而言，中心假设的确认将产生重大影响。对于该领域来说，它将提供关于中间神经元在 HD 中的交叉作用的有力证据发病机制，并确定了预防 HD 发病和进展的新型早期治疗窗口针对目前缺乏实质性和有效治疗干预措施的神经退行性疾病。