Synaptic toxicity of Huntington disease protein

亨廷顿病蛋白的突触毒性

基本信息

批准号：
8516918
负责人：
XIAO-JIANG LI
金额：
$ 29.9万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-05-01 至 2017-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Synaptic toxicity of the Huntington's disease protein Huntington's disease (HD) is caused by polyglutamine (polyQ) expansion in the N- terminal region of huntingtin (htt). It is characterized by progressive neurodegeneration that preferentiall affects the medium spiny neurons in the striatum. Furthermore, polyQ expansion leads to ht becoming misfolded and aggregated in an age-dependent manner. Thus, HD and other aging-related neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, share the major features of late-onset and selective neurodegeneration, as well as age-dependent protein aggregation. Because of its well-defined genetic mutation and neuropathology, HD makes an ideal system for investigating the pathogenesis of age-dependent neurodegenerative diseases. Moreover, numerous studies have shown that mutant htt can impair synaptic function, an early neuropathologic event that is also common in many other age-dependent neurological disorders. Despite the fact that mutant ht can affect a variety of synaptic functions, how exactly synaptic dysfunction contributes to HD neuropathology remains unclear. We also do not know how mutant htt can preferentially accumulate in the axons of medium spiny neurons in HD knock-in (KI) mice that express full-length mutant htt. Since it is medium spiny neurons that are mostly affected in HD, understanding the mechanism for this preferential accumulation is important to unravel the pathogenesis of HD and develop treatments for the early neuropathology of HD. We hypothesize that mutant N-terminal htt fragments may interact abnormally with axonal proteins to preferentially accumulate in axonal terminals of medium spiny neurons and affect synaptic function. To test these hypotheses, we have generated a novel transgenic HD mouse model that selectively expresses N-terminal mutant htt in axonal terminals. Using this HD mouse model, we will explore whether axonal terminal mutant htt can cause neurological symptoms and affect synaptic function, as well as identify the common pathological events that also occur in HD KI mice. We will then examine whether and how N-terminal mutant htt fragments can preferentially accumulate in axons and affect the function of medium spiny neurons by identifying the axonal proteins that may abnormally interact with mutant htt. These studies also have implications for our understanding of synaptic dysfunction in other age-dependent neurodegenerative diseases that are also caused by misfolded proteins.

描述（由申请人提供）：亨廷顿舞蹈病蛋白的突触毒性亨廷顿舞蹈病（HD）是由亨廷顿舞蹈病（htt）的N-末端区域中的聚谷氨酰胺（polyQ）扩张引起的。其特征是进行性神经变性，优先影响纹状体中的中型多棘神经元。此外，polyQ 扩展导致 ht 错误折叠并以年龄依赖性方式聚集。因此，HD和其他与衰老相关的神经退行性疾病，例如帕金森病和阿尔茨海默病，具有迟发性和选择性神经退行性变以及年龄依赖性蛋白质聚集的主要特征。由于其明确的基因突变和神经病理学，HD 成为研究年龄依赖性神经退行性疾病发病机制的理想系统。此外，大量研究表明，突变型 htt 会损害突触功能，这是一种早期神经病理事件，在许多其他年龄依赖性神经系统疾病中也很常见。尽管突变 ht 可以影响多种突触功能，但突触功能障碍究竟如何影响 HD 神经病理学仍不清楚。我们也不知道突变体 htt 如何优先积聚在表达全长突变体 htt 的 HD 敲入 (KI) 小鼠的中型多棘神经元的轴突中。由于 HD 中最受影响的是中型棘神经元，因此了解这种优先积累的机制对于阐明 HD 的发病机制并开发 HD 早期神经病理学的治疗方法非常重要。我们假设突变的 N 端 htt 片段可能与轴突蛋白异常相互作用，优先积聚在中型多棘神经元的轴突末端并影响突触功能。为了测试这些假设，我们构建了一种新型转基因 HD 小鼠模型，该模型在轴突末端选择性表达 N 端突变体 htt。利用这种 HD 小鼠模型，我们将探讨轴突末端突变体 htt 是否会引起神经症状并影响突触功能，并确定 HD KI 小鼠中也发生的常见病理事件。然后，我们将通过鉴定可能与突变 htt 异常相互作用的轴突蛋白来检查 N 端突变 htt 片段是否以及如何优先在轴突中积累并影响中型多棘神经元的功能。这些研究也有助于我们理解其他年龄依赖性神经退行性疾病中的突触功能障碍，这些疾病也是由错误折叠的蛋白质引起的。