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

帕金森病是一种无法治愈的神经退行性疾病，约占全球65岁以上人口的1-2%，随着人口老龄化，其患病率预计将进一步增加。这种毁灭性和致命疾病的症状包括震颤、僵硬和自主运动缓慢。目前，虽然有一些治疗方法可以减少这些高度衰弱的症状，但没有一种治疗方法可以显著改变疾病本身的进程。由于我们缺乏对患病大脑中发生的分子过程的了解，治疗方法的发展受到阻碍。在这种疾病中受损最严重的大脑区域包含一种叫做α -突触核蛋白的线状蛋白质集合，形成被称为路易小体的沉积物。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体是否确实导致了脑细胞的损失。对这些聚集体的结构特性的详细了解仍然缺失，但它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质（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，从而使我们能够控制这些不同类型聚集体的形成。通过使用这些小抗体结构域来控制α -突触核蛋白在细胞、蠕虫和果蝇大脑中的聚集，我们将测量是否有任何小抗体结构域能够预防α -突触核蛋白引起的神经退行性变。将这些生物体的观察结果与试管中抗体结构域的影响进行比较，将使我们能够确定哪种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 -突触核蛋白聚集有关的疾病的最佳靶点，通常称为突触核蛋白病。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，例如阿尔茨海默病和传染性海绵状脑病，包括痒病和疯牛病，这些疾病同样对公共卫生和经济产生重大影响。

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.