Glucocerebrosidase mutations in Parkinson disease:molecular pathogenesis,and the basis for personalised therapy with small molecule chaperones

帕金森病(PD)是仅次于阿尔茨海默病的第二大神经退行性疾病。确诊的高峰年龄是62岁，但帕金森病患者的数量随着年龄的增长而上升：75岁为3100/10万，85岁为4300/100,000。在英国，帕金森病的终生风险目前为3-4%。目前，帕金森病的所有治疗都是对症治疗，并不能延缓疾病的进展。人们迫切需要一种可以减缓或阻止疾病的药物。有许多原因和因素会增加帕金森病的风险，但GBA基因的突变是最重要的。该基因的突变使帕金森病的风险增加了20-30倍，至少在10%的帕金森病患者中被发现。对帕金森病死亡患者的大脑、细胞模型和GBA突变与帕金森病的动物模型的研究表明，GBA基因的产物葡萄糖脑苷酶GCase和参与帕金森病病理的主要蛋白质-α-突触核蛋白(SNCA)之间存在密切联系。这种关系是互惠的，例如，由于GBA基因突变而导致的GCase活性降低，会导致SNCA的增加--就像在帕金森病中看到的那样。或者，SNCA增加，例如SNCA基因突变的结果，导致GCase活性降低。重要的是，我们和其他人已经在人类细胞和动物模型中表明，这种关系可以被操纵，从而增加GCase活性导致SNCA水平降低。这与PD有相当大的相关性，并提供了开发针对这种关系的新药并降低SNCA水平和扩散以减缓或阻止PD进展的机会。该项目旨在解决GCase-SNCA关系的重要特征，为PD患者在这一领域的临床试验做准备。人类研究动物研究小分子伴侣增加GCase-这减少了SNCA未来的人类研究在一项试点研究中，我们使用了一种目前可用于治疗完全不同疾病的患者的药物，该药物在PD患者的人类细胞中具有非常好的安全性，以表明它可以提高GCase的活性。这种药物是一种被称为小分子伴侣的药物，它与GCase相互作用，并增加这种酶的突变形式和正常形式的活性。同样，我们的初步研究已经证实，这种药物可以降低神经细胞中SNCA的水平。因此，我们准备进入下一个阶段，为PD患者开发这一药物类别。在我们进行人体研究之前，我们需要在患有和不患有帕金森病的GBA突变患者的细胞培养中进一步测试该药物。这一结果将证实小分子伴侣具有提高GCase活性的作用。我们还将分析GBA突变如何增加帕金森病的风险，以及个人的症状和体征如何表明他们患上这种疾病的风险。这对于识别有风险的人以及在PD发展之前谁最适合接受药物治疗将是非常重要的。此外，在进入人体研究之前，我们需要在动物模型中确认上述假设方程的第二部分。我们需要确认药物对大脑SNCA的影响，以降低SNCA的水平，并潜在地降低SNCA病理的传播。如果这里概述的研究结果是积极的，我们的试点数据强烈表明它们将是积极的，下一阶段将进入帕金森病患者的临床试验，同时，与行业合作开发新型高活性小分子伴侣，用于进一步的患者测试和使用。

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease. Peak age of diagnosis is 62 years, but number of people with PD rises with age: 3100/100,000 >75 years and 4300/100,000 >85 years. The lifetime risk for PD in the UK is currently 3-4%. At present, all treatment for PD is symptomatic, it does not slow down the progression of the disease. A drug that can slow or stop the disease is desperately needed.There are many causes and factors that increase the risk of PD, but mutations of the GBA gene are the most important. Mutations of this gene increase the risk for PD by 20-30 times, and are found in at least 10% of PD cases.Studies of brains from patients who have died with PD, cell models and animal models of GBA mutations and PD indicate that there is a close link between glucocerebrosidase enzyme GCase, the product of the GBA gene and alpha-synuclein (SNCA), the main protein involved in PD pathology. This relationship is reciprocal in that reduced GCase activity, for instance as a consequence of a mutation in the GBA gene, causes an increase in SNCA - such as is seen in PD. Alternatively, increased SNCA, for instance as a consequence of mutations in the SNCA gene, result in a reduction in GCase activity. Importantly, we and others have shown in human cells and animal models that this relationship can be manipulated so that increasing GCase activity induces a reduction in SNCA levels. This is of considerable relevance to PD, and offers the opportunity to develop novel drugs to target this relationship and decrease SNCA levels and spread to slow or stop the progression of PD.This project is designed to address important features of the GCase-SNCA relationship in preparation for clinical trials in this area in PD patients. human studies animal studies SMALL MOLECULE CHAPERONE increases GCase------which reduces SNCA future human studiesIn a pilot study we have used a drug currently available for use in patients for an entirely different illness and with a very good safety profile, in human cells from PD patients to show that it can increase GCase activity. This drug is a class known as a small molecule chaperone that interacts with GCase and increases activity of both the mutant and normal forms of this enzyme. Similarly our pilot studies have confirmed that this drug can reduce SNCA levels in neuronal cells. Thus we are poised to enter the next stage towards developing this drug class for PD patients. Before we move to human studies we need to test the drug further in cell cultures from individuals with GBA mutations, with and without PD. The results will confirm the effect of small molecule chaperones to increase GCase activity. We will also be analysing how GBA mutations increase the risk of PD and how an individual's symptoms and signs can signal their risk for the disease. This will be very important in identifying those at risk and who would be best suited to receive a drug prior to the development of PD.In addition, before moving to human studies we need to confirm the second part of the hypothesis equation above in an animal model. We need to confirm the effect of the drug on brain SNCA to reduce levels and potentially the spread of SNCA pathology. If the results of the studies outlined here are positive, and our pilot data strongly indicate they will be, the next stage will be to move towards clinical trial in PD patients, and in parallel, to collaborate with industry to develop novel highly active small molecule chaperones for further testing and use in patients.