Interneurons as Early Drivers of Huntington´s Disease Progression

亨廷顿病(HD)是一种由三核苷酸重复序列扩增引起的潜伏性神经退行性疾病 在编码亨廷顿(MHTT)的基因的外显子1上。HD的致病机制仍然不清楚。 明白了。对HD模型的研究已经记录了许多发育障碍 清单‘高清。使用有条件的HD模型，Mehler实验室团队之前已经证明了这样的 发育过程在疾病发病机制中起中介作用。现在，这个团队提供的证据表明 在HD小鼠模型中，神经元间神经发生明显中断，导致补体缺陷 在发育中的大脑皮层内的这些中间神经元。这些缺陷是非常重要的，因为研究 已经证明这些会导致皮质-纹状体连接的永久性变化，为大脑皮质 过度兴奋，兴奋-抑制偶联受损，以及晚年纹状体兴奋毒性应激。虽然 先前曾报道过HD患者皮质间神经元缺陷，但它们在HD发病机制中的作用从未见过 被进一步审问。这个应用程序测试了中心假设，即HD是由大脑 选择性皮质中间神经元亚型的发育性阐述；因此，预防 这些中间神经元缺陷的发育效应将改善甚至预防疾病的发生。这 初步数据表明，发育中的中间神经元的遗传挽救进一步支持了这一假说 阻止BACHD小鼠出现HD的特征：运动协调障碍，髓鞘减少 皮质下白质束和纹状体变性。特定目标1(SA1)最初定义 异种异体移植对突变型新生仔鼠神经元祖细胞的补充效果良好 改善运动障碍和纹状体变性的发生，这是HD的两个显著特征。这个目标也是 检查中间神经元在疾病进展中的作用是否以定量的 缺陷或通过与突变的亨廷顿蛋白在这些细胞中的表达相关的额外因素。SA2 询问介导HD的中间神经元依赖的致病机制，重点是推测的调制 GABA、Reelin和互补配体释放的影响。最后，SA3采用了大量的硬盘阵列 来自两个主要脑库的尸检样本以确定皮质在疾病进展中的作用 中间神经元缺陷。这一目的还询问了已知的HD遗传修饰物，包括三核苷酸 DNA损伤反应基因的扩展长度和/或多态性调节中间神经元的程度 改变，以及这些细胞是否介导了这些遗传修饰物对年龄的预测作用 疾病的发生/发展。总体而言，对中心假设的确认将产生重大影响 因为这将为HD中神经元间的交叉作用提供强有力的证据 发病机制，并为预防HD的发生和进展定义了一个新的早期治疗窗口 目前缺乏实质性和有效的治疗干预的神经退行性疾病。

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.