Synaptic toxicity of Huntington disease protein

亨廷顿病蛋白的突触毒性

• 批准号: 8894345
• 负责人: XIAO-JIANG LI
• 金额: $ 30.69万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894345
• 关键词: Affect; Alzheimer' s Disease; Axon; Binding; Cell Nucleus; Cleaved cell; Corpus striatum structure; DNA Sequence Alteration; Disease; Early treatment; Event; Exocytosis; Functional disorder; Gene Expression; Gene Mutation; Globus Pallidus; Huntington Disease; Knock-in Mouse; Length; Mediating; Mus; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Parkinson Disease; Pathogenesis; Pathology; Proteins; Proteomics; Recycling; Symptoms; Synapses; Synaptic Vesicles; Synaptosomes; System; Testing; Therapeutic; Toxic effect; Transgenic Organisms; age related; cell type; human Huntingtin protein; in vivo; mouse model; mutant; nervous system disorder; neuropathology; neurotransmission; novel; polyglutamine; progressive neurodegeneration; protein aggregation; protein misfolding; selective expression; synaptic function; therapeutic target

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）：亨廷顿疾病蛋白亨廷顿氏病（HD）的突触毒性是由亨廷顿（HTT）N-末端区域的聚谷氨酰胺（PolyQ）膨胀引起的。它的特征是进行性神经变性，优先级会影响纹状体中的中棘神经元。此外，polyq的扩展会导致HT以年龄依赖性的方式被错误折叠和汇总。因此，HD和其他与衰老有关的神经退行性疾病（例如帕金森氏症和阿尔茨海默氏病）具有后期和选择性神经变性的主要特征，以及依赖年龄的蛋白质聚集。由于其定义明确的遗传突变和神经病理学，HD是研究年龄依赖性神经退行性疾病发病机理的理想系统。此外，许多研究表明，突变体HTT会损害突触功能，这是一种早期的神经病理事件，在许多其他年龄依赖性神经系统疾病中也很常见。尽管突变体HT可能会影响各种突触功能，但仍然尚不清楚突触功能障碍如何促进HD神经病理学。我们也不知道如何在表达全长突变体HTT的HD敲入（Ki）小鼠中的中棘神经元的轴突中优先积聚。由于它是中刺神经元主要受到HD的影响，因此了解这种优先积累的机制对于揭示HD的发病机理并为HD早期神经病理发展治疗很重要。我们假设突变的N末端HTT片段可能与轴突蛋白异常相互作用，以优先积聚在中棘神经元的轴突末端并影响突触功能。为了检验这些假设，我们生成了一种新型的转基因HD小鼠模型，该模型在轴突末端有选择地表达N末端突变体HTT。使用此HD小鼠模型，我们将探索轴突末端突变体HTT是否会引起神经系统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，我们将检查以及如何以及如何通过鉴定可能异常与突变体HTT相互作用的轴突蛋白来优先积聚轴突中的N末端突变体HTT片段。这些研究也对我们对其他依赖性神经退行性疾病中突触功能障碍的理解也具有影响，这些神经退行性疾病也是由错误折叠蛋白引起的。