Conditional Models: non-cell-autonomous Toxicities in HD

描述（由主要研究者提供）：亨廷顿病（HD）是最常见的显性遗传性神经退行性疾病之一，在美国影响30，000例患者，另有150，000例患者处于风险中。HD的特征在于运动、认知和精神症状，这些症状通常进展并导致患者在疾病发作后约10-20年内死亡。HD是由突变体亨廷顿中的多聚谷氨酰胺重复扩增引起的，导致主要靶向纹状体神经元但也影响皮质神经元的神经变性的持续进展。目前，没有治疗或治愈HD的方法。由于突变型亨廷顿蛋白（mhtt）在大脑和身体中广泛表达，但HD中的神经元变性主要针对纹状体和皮质神经元，因此HD中一个关键但尚未回答的问题是广泛分布的mhtt如何导致神经元变性的选择性模式？为了解决这个问题，我们首先要问mhtt表达在疾病发病机制中的关键位置。使用一系列新的HD小鼠模型，可以在大脑中的不同类型的细胞中表达mhtt或其毒性片段，我们发现mhtt片段不仅可以诱导其表达的神经元的内在毒性，而且可以诱导不同类型的神经元之间的毒性相互作用。此外，我们发现，关闭mhtt表达在皮层神经元的结果在一个显着的，但部分救援的行为缺陷和纹状体毒性在HD小鼠。这些令人兴奋的发现强调了研究皮质和纹状体神经元是否以及如何共同作用以引起HD的必要性。我们设计了以下目标来解决这个关键问题：目标1。纹状体中mhtt的表达是HD发病机制所必需的吗？目标2.关闭皮质和纹状体的全长mhtt表达是否能协同减少HD小鼠的关键疾病表型？目标3。仅在皮质锥体神经元和纹状体中等多棘神经元中的全长mhtt的转换是否足以诱导体内HD表型的关键方面？我们的研究的完成可能揭示mhtt是否从两种类型的神经元（即纹状体和皮质神经元）内发挥协同毒性作用，以引起HD的主要疾病表型。我们的研究可能支持HD致病机制在这两种细胞类型的分子解剖，并可能进一步告知我们的最佳策略，局部交付的mhtt减少治疗（即RNA干扰，反义寡核苷酸或胞内抗体）。

DESCRIPTION (provided by principal investigator): Huntington's disease (HD) is one of the most common dominantly inherited neurodegenerative disorders affecting 30,000 patients in the US with another 150,000 at risk. HD is characterized by motor, cognitive and psychiatric symptoms that often progress and result in the patient's death in about 10-20 years after disease onset. HD is caused by a polylgutamine repeat expansion in mutant Huntington, resulting in the relentless progression of neurodegeneration primarily targeting the striatal neurons but also affecting the cortical neurons. Currently, there is no treatment or cure for HD. Since mutant huntingtin (mhtt) is widely expressed in the brain and in the body but neuro degeneration in HD primarily targets the striatal and cortical neurons, a critical yet unanswered question in HD is how does the widely distributed mhtt cause such selective patterns of neuro degeneration? To address this question, we first will ask where mhtt expression is critical for disease pathogenesis. Using a novel series of HD mouse models that can express mhtt or its toxic fragments in different types of cells in the brain, we discovered that mhtt fragments can induce not only the intrinsic toxicities to the neurons in which it is expressed but also toxic interactions between different types of neurons. Furthermore, we found that switching off mhtt expression in the cortical neurons results in a significant but partial rescue of both the behavioral deficits and striatal toxicities in HD mice. These exciting findings underscore the need to study whether and how the cortical and striatal neurons may act together to elicit HD. We designed the following aims to address this critical question: Aim 1. Is mhtt expression in the striatum necessary for HD pathogenesis? Aim 2. Can switching off full length mhtt expression in both the cortex and striatum synergically reduce key disease phenotypes in HD mice? Aim 3. Can switching of full length mhtt only in the cortical pyramidal neurons and striatal medium spiny neurons be sufficient to induce key aspects of HD phenotypes in vivo? The completion of our study may reveal whether mhtt exert synergistic toxic effects from within two types of neurons (i.e. the striatal and cortical neurons) to elicit the major disease phenotypes in HD. Our study may support the molecular dissection of HD pathogenic mechanisms in these two cell types, and may further inform us on the optimal strategies of local delivery of mhtt reducing therapeutics (i.e. RNA interference, antisense oligonucleotides or intrabodies).