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神经退行性疾病 在编码亨廷顿蛋白（mHtt）的基因的外显子1中。HD的致病机制仍然不清楚 明白HD模型的研究已经记录了许多发育障碍， manifest高清使用条件HD模型，Mehler实验室团队先前已经证明， 发育过程介导疾病的发病机制。现在，这个团队提供的证据表明， 在HD小鼠模型中，中间神经元神经发生显著中断，导致补体缺乏， 这些中间神经元在发育中的大脑皮层。这些缺陷是非常重要的，因为研究 已经表明这些导致皮质-纹状体连接的永久性变化，为皮质-纹状体连接的形成奠定了基础。 兴奋过度、兴奋-抑制偶联受损和生活后期的纹状体兴奋毒性应激。虽然 以前曾报道过HD病例中存在皮质中间神经元缺陷，但从未报道过它们在HD发病机制中的作用。 被进一步审问。该应用程序测试了中心假设，即HD是由以下因素引起的： 选择性皮质中间神经元亚型的发育加工;因此， 这些中间神经元缺陷的发育效应将改善或甚至预防疾病的发生。这 初步数据进一步支持了这一假设，这些数据表明，发育中中间神经元的遗传拯救 排除了BACHD小鼠中HD特征性特征的发作：运动协调缺陷、髓鞘形成不足 皮质下白色物质束和纹状体退化的迹象具体目标1（SA 1）最初定义是否 通过异时移植向突变新生幼崽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的两个独特特征。这一目标还 检查是否中间神经元在疾病进展中的作用是以定量为代价的。 缺陷或通过与这些细胞中突变亨廷顿蛋白表达相关的额外因素。SA2 询问介导HD的中间神经元依赖性致病机制，重点是假定的调节 GABA、Reelin和互补配体释放的影响。最后，SA 3采用了一个大的HD阵列， 来自两个主要脑库的尸检标本，以确定皮层神经元在疾病进展中的作用。 中间神经元缺陷这一目的也询问是否已知的HD遗传修饰剂，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程度， 改变，以及这些细胞是否介导这些遗传修饰剂对年龄的预测作用。 疾病发作/进展。总的来说，对中心假设的确认将产生重大影响 为该领域，因为它将提供强有力的证据，中间神经元在HD中的交叉作用 发病机制，并确定了一个新的早期治疗窗口，以防止HD的发病和进展 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.