Probing the molecular origins of Parkinsons disease using camel single domain antibodies

使用骆驼单域抗体探索帕金森病的分子起源

• 批准号: G1002272/1
• 负责人: Christopher Dobson
• 金额: $ 48.96万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1002272%2F1
• 关键词: Probing; molecular; origins; Parkinsons; disease

Parkinsons disease is an incurable neurodegenerative condition that afflicts about 1-2% of the global population over 65 years, and whose prevalence is expected to increase even further as our population ages. The symptoms of this devastating and fatal disease include tremor, rigidity, and slowness of voluntary movements. Currently, although there are treatments to reduce these highly debilitating symptoms, no cure is available that can alter significantly the course of the disease itself. The development of a cure is hampered by our lack of understanding of the molecular processes occurring in the diseased brain. The regions of the brain that are most damaged in the disease contain thread-like assemblies of a protein called alpha-synuclein, which form deposits known as Lewy bodies. Although a clear link exists between the presence of these deposits and the disease, it is not clear whether these or other smaller aggregates are actually responsible for the loss of brain cells. A detailed understanding of the structural properties of these aggregates is still missing, but it would be vital for enabling the development of therapeutic strategies. The introduction of novel tools to control the populations of these aggregates is of great importance for their structural investigation and for identifying the species that are most toxic to brain cells. We have designed a type of small proteins (called antibody domains) that can bind to alpha-synuclein in different ways and that allow us to control the formation of these different types of aggregates. By employing these small antibody domains to control the aggregation of alpha-synuclein in cells, worms and in the brain of fruit flies, we will measure whether any of the small antibody domains are able to prevent the neurodegeneration caused by alpha-synuclein. The comparison of the observations in these organisms with those on the effects of the antibody domains in the test tube will allow us to identify which types of aggregates are most important in the development of Parkinsons disease and hence represent the best targets for developing therapies to treat or prevent this disease and other diseases related to the aggregation of alpha-synuclein, generally termed synucleinopathies. The knowledge gained from the proposed research will also contribute considerably to the advances in the elucidation of other protein aggregation disorders, such as Alzheimers disease, and the transmissible spongiform encephalopathies, including scrapie and the mad cow disease, which equally have a high impact on public health and economy.

帕金森病是一种无法治愈的神经退行性疾病，在65年内折磨着全球约1-2%的人口，随着人口老龄化，其患病率预计将进一步增加。这种毁灭性和致命性疾病的症状包括震颤，僵硬和随意运动缓慢。目前，虽然有治疗方法可以减少这些高度衰弱的症状，但没有治愈方法可以显着改变疾病本身的过程。我们对患病大脑中发生的分子过程缺乏了解，阻碍了治疗方法的发展。在这种疾病中受损最严重的大脑区域含有一种叫做α-突触核蛋白的蛋白质的线状组装体，这种蛋白质形成了被称为路易体的沉积物。虽然这些沉积物的存在与疾病之间存在明确的联系，但尚不清楚这些或其他较小的聚集物是否真的导致脑细胞的损失。对这些聚集体的结构特性的详细了解仍然缺失，但这对于开发治疗策略至关重要。引入新的工具来控制这些聚集体的数量对于它们的结构研究和识别对脑细胞毒性最大的物种具有重要意义。我们设计了一种小蛋白（称为抗体结构域），它可以以不同的方式与α-突触核蛋白结合，使我们能够控制这些不同类型的聚集体的形成。通过使用这些小的抗体结构域来控制α-突触核蛋白在细胞、蠕虫和果蝇脑中的聚集，我们将测量任何小的抗体结构域是否能够防止由α-突触核蛋白引起的神经变性。这些生物体中的观察结果与试管中抗体结构域的影响的比较将使我们能够确定哪些类型的聚集体在帕金森病的发展中最重要，因此代表了开发治疗或预防这种疾病和其他与α-突触核蛋白聚集相关的疾病（通常称为突触核蛋白病）的最佳靶点。从拟议的研究中获得的知识也将大大有助于在阐明其他蛋白质聚集障碍方面取得进展，如阿尔茨海默病和传染性海绵状脑病，包括羊瘙痒症和疯牛病，这些疾病对公共卫生和经济也有很大影响。