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

帕金森病（Parkinson disease，PD）是仅次于阿尔茨海默病（Alzheimer disease，AD）的第二大神经退行性疾病。诊断的高峰年龄为62岁，但PD患者人数随年龄增加而增加：3100/100，000> 75岁和4300/100，000> 85岁。在英国，PD的终身风险目前为3 - 4%。目前，PD的所有治疗都是对症治疗，不能减缓疾病的进展。帕金森病的病因和危险因素很多，但GBA基因突变是最重要的。该基因的突变使PD的风险增加20 - 30倍，并且在至少10%的PD病例中发现。对死于PD的患者的大脑、GBA突变和PD的细胞模型和动物模型的研究表明，GBA基因的产物葡萄糖脑苷脂酶GCase和参与PD病理学的主要蛋白质α-突触核蛋白（SNCA）之间存在密切联系。这种关系是相互的，因为GCase活性降低，例如由于GBA基因突变，导致SNCA增加-如在PD中所见。或者，增加的SNCA，例如作为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活性诱导SNCA水平降低。这是相当相关的PD，并提供了机会，开发新的药物，以针对这种关系，并降低SNCA水平和蔓延，以减缓或停止PD的进展。该项目旨在解决的重要特征GCase-SNCA关系，在准备在这方面的临床试验在PD患者。在一项初步研究中，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，该药物具有非常好的安全性，在PD患者的人体细胞中显示它可以增加GCase活性。这种药物是一类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体和正常形式的活性。同样，我们的初步研究证实，这种药物可以降低神经元细胞中的SNCA水平。因此，我们准备进入下一阶段，为PD患者开发这类药物。在我们进入人体研究之前，我们需要在GBA突变个体的细胞培养物中进一步测试药物，有和没有PD。结果将证实小分子伴侣对增加GCase活性的作用。我们还将分析GBA突变如何增加PD的风险，以及个体的症状和体征如何表明其疾病风险。这将是非常重要的，在确定那些在风险和谁将是最适合接受药物之前，PD的发展。此外，在转移到人体研究，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病理的水平和潜在的传播。如果本文概述的研究结果是积极的，并且我们的试点数据强烈表明它们将是积极的，那么下一阶段将是在PD患者中进行临床试验，同时与行业合作开发新型高活性小分子分子伴侣，以进一步测试和用于患者。

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.