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

帕金森病（PD）的终生风险为3- 4%，欧盟每年约有60，000例新发病例。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脂酶1（GBA 1）突变在数字上是PD最重要的风险因素。它们在10-15%的PD中被发现（在德系犹太人中为25%），并使PD的风险增加20- 30倍。PD涉及脑细胞（神经元）的损失和称为α-突触核蛋白（a-syn）的蛋白质的积累。GBA 1突变导致葡糖脑苷脂酶（GCase）的活性受损，该酶参与不需要或多余细胞成分（包括蛋白质）的正常分解。已经显示，GBA 1突变和降低的GCasae活性导致α-syn浓度增加。有趣的是，α-syn的积累导致正常酶中GCase活性受损。因此，在GCase活性和α-syn水平之间存在强的相互关系。在此基础上，认为导致GCase抑制的GBA 1突变启动了GCase缺陷和α-syn积累的自放大循环，导致PD。这反映在那些携带GBA 1突变和发展PD的发病早，更快的进展比那些没有GBA 1突变。在这个项目中，我们将调查的演变之前和期间的临床特征，PD在那些携带GBA 1突变。参与者可以访问具有GBA 1突变的人群，有和没有PD（>700 un UK）。我们将整合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及其如何演变为临床PD。我们还将收集用于生物标志物分析的样本，以便我们可以将这些样本与临床特征结合联合收割机，以确定队列中最有可能发生PD的患者。患者将被要求提供皮肤刮擦，以便我们可以培养这些细胞，并通过既定的协议将它们转化为多巴胺能神经元-PD中首先退化的类型。这些干细胞衍生的模型将用于研究GBA 1突变的细胞生物化学效应的特定方面，以了解与增加的α-syn水平相关的基础。作为该研究的一部分，我们将开发一种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GBA 1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，也将用于测试化合物（氨溴索）是否能够逆转GBA 1突变的影响。盐酸氨溴索是一种与突变GCase结合并将其递送到细胞内正确位置（溶酶体）的分子。它是一种被重新利用的药物，目前作为止咳灵在销售。在细胞、干细胞、苍蝇和动物模型中，氨曲索能够增加GBA 1突变模型中的GCase活性，并降低a-syn水平。因此，它代表了一种有前途的化合物，用于未来的研究，作为一种潜在的药物，以减缓PD。

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.