JPND GBA - personalised medicine for Parkinson disease: clinical and therapeutic stratification

帕金森病（PD）的终生风险为3-4%，在欧盟每年约有6万例新病例。在欧盟，所有与pd相关的费用估计为每年130亿欧元。PD的最新进展已经确定葡萄糖脑苷酶1 （GBA1）突变是PD最重要的危险因素。它们在10-15%的PD（德系犹太人中为25%）中发现，并使PD的风险增加20-30倍。PD包括脑细胞（神经元）的损失和α -突触核蛋白（a-syn）蛋白质的积累。GBA1突变导致葡萄糖脑苷酶（GCase）活性受损，GCase参与不需要或多余的细胞成分（包括蛋白质）的正常分解。研究表明，GBA1突变和GCasae活性降低导致a-syn浓度增加。有趣的是，a-syn的积累导致正常酶的GCase活性受损。因此，GCase活性和a-syn水平之间存在很强的互反关系。在此基础上，我们认为导致GCase抑制的GBA1突变启动了GCase缺乏和a-syn积累的自我放大周期，从而导致PD。这反映在那些携带GBA1突变的人身上，他们比没有GBA1突变的人发病更早，进展更快。在这个项目中，我们将研究携带GBA1突变的人在PD发生之前和发展过程中临床特征的演变。参与者可以进入GBA1突变的人群，有或没有PD（在英国有700人）。我们将整合在英国队列中开发的基于网络的临床评估与意大利和西班牙的评估，以了解前驱特征的模式以及它们如何演变为临床PD。我们还将收集样本进行生物标志物分析，这样我们就可以将这些样本与临床特征相结合，以确定那些最有可能患帕金森病的人群。患者将被要求提供皮肤擦伤，这样我们就可以培养这些细胞，并通过既定的方案将它们转化为多巴胺能神经元——PD患者首先退化的类型。这些干细胞衍生的模型将用于研究GBA1突变的细胞生化效应的特定方面，以了解与a-syn水平增加相关的基础。作为这项研究的一部分，我们将开发一个三维多巴胺能神经元的高级模型，即所谓的脑类器官。这些模型对于理解a-syn从一个神经元到另一个神经元的空间传播是有价值的。我们假设GBA1突变会加速a-syn的传播。我们的干细胞衍生模型，包括类器官，也将用于测试一种化合物（氨溴索）是否能够逆转GBA1突变的影响。氨溴索是一种与突变GCase结合并将其运送到细胞内正确位置（溶酶体）的分子。这是一种改头换面的药物，目前作为止咳药出售。在细胞、干细胞、苍蝇和动物模型中，氨硝索能够增加GBA1突变模型中的GCase活性，并降低a-syn水平。因此，它作为一种潜在的减缓帕金森病的药物，在未来的研究中具有广阔的前景。

Parkinson disease (PD) has a lifetime risk of 3-4%, and there are approximately 60,000 new cases annually in the EU. All PD-related costs in the EU are estimated at 13 billion euros per annum. Recent advances in PD have identified that glucocerebrosidase 1 (GBA1) mutations are numerically the most important risk factor for PD. They are found in 10-15% of PD (25% in Ashkenazi Jews), and increase the risk for PD by 20-30x.PD involves the loss of brain cells (neurons) and the accumulation of a protein called alpha-synuclein (a-syn). GBA1 mutations cause impaired activity of the glucocerebrosidase enzyme (GCase) that is involved in the normal breakdown of unwanted or redundant cell constituents, including proteins. It has been shown that GBA1 mutations and reduced GCasae activity result in an increase in a-syn concentrations. Intriguingly, accumulation of a-syn causes impaired GCase activity in the normal enzyme. Thus there is a strong reciprocal relationship between GCase activity and a-syn levels. On this basis, it is considered that the GBA1 mutations that lead to GCase inhibition, initiate a self-amplifying cycle of GCase deficiency and a-syn accumulation that causes PD. This is reflected in those that carry GBA1 mutations and develop PD by their earlier onset and more rapid progression than those without GBA1 mutations.In this project we will investigate the evolution of clinical features prior to and during the development of PD in those that carry GBA1 mutations. The participants have access to cohorts of those with GBA1 mutations, with and without PD (>700 un the UK). We will integrate the web-based clinical assessments developed in the UK cohort with those in Italy and Spain to understand the pattern of prodromal features and how they evolve to clinical PD. We will also collect samples for biomarker analysis so that we can combine these with the clinical characteristics to identify those within the cohorts who are most at risk for the development of PD. Patients will be asked to provide skin scrapes so that we can culture these cells and convert them through an established protocol, into dopaminergic neurons - the type that degenerate first in PD. These stem cell derived models will be used to investigate specific aspects of the cellular biochemical effects of GBA1 mutations to understand the basis of the link with increased a-syn levels. as part of this we will develop an advnced model of the dopaminergic neurons in 3-dimensions, a so-called brain organoid. These models are valuable to understand the spatial spread of a-syn from one neuron to another. We hypothesise that GBA1 mutations will accelerate the spread of a-syn.Our stem-cell derived models, including the organoids will also be used to test whether a compound (ambroxol) is capable of reversing the effects of GBA1 mutations. Ambroxol is a molecule that binds to mutatant GCase and delivers it to its correct location within the cell (the lysosome). It is an a repurposed drug, currently on sale as a cough linctus. In cell, stem cell, fly and animal models, amroxol has been able to increase GCase activity in GBA1 mutation models, and reduce a-syn levels. Therefore it represents a promising compound for future investigation as a potential drug to slow PD.