In vivo pathway analysis to determine the mechanistic role of susceptibility genes for Parkinson's disease

体内途径分析以确定帕金森病易感基因的机制作用

• 批准号: MR/R011354/1
• 负责人: Oliver Bandmann
• 金额: $ 63.77万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR011354%2F1
• 关键词: vivo; pathway; analysis; determine; mechanistic

Parkinson's disease (PD) is a common and relentlessly progressive brain disease. Its key symptom, slowness of movement, is caused by the death of nerve cells (neurons) that produce a chemical called dopamine in a part of the brain called the substantia nigra. Currently available therapies are inadequate: Firstly, they treat only some, but not all, of the symptoms of the disease. Secondly, they do not modify the underlying disease processes and therefore fail to slow down disease progression. This failure is partially due to our limited knowledge of the mechanisms that cause PD. Over the last 20 years, there has been huge progress with the identification of genes and mechanisms which cause PD that is inherited due to faults (mutations) in genes (familial PD). However, only about 5-10% of PD patients in the UK carry such a familial PD mutation. This project aims to elucidate how inherited factors contribute to the risk of the much more common sporadic form of PD. So-called genome-wide association studies (GWAS) have now identified 24 regions within our genome which contain genes that contribute to the risk of sporadic PD. However, it is not clear how these genes contribute to the risk of PD and, in some cases, which particular gene within such a region is responsible. Our aim is to study those genes which are most likely to contribute to the risk of PD (from hereon called PD GWA genes). We and others believe that these genes will be involved in 3 distinct mechanisms, namely:1) The regulation of energy production and energy maintenance (homeostasis) by cellular components called mitochondria.2) The aggregation and breakdown of proteins by processes called autophagy and cellular components called lysosomes.3) Inflammation (the cellular response to injury and infection). We propose to use zebrafish carrying gene defects which will inactivate these PD GWA genes for our studies. Zebrafish are vertebrates and therefore much more closely related to humans then other lower animal models such as worms or fruit flies. They also offer the opportunity to study the interaction of PD GWA genes with ageing processes. This is important since ageing is the most important risk factor for PD. Zebrafish larvae develop outside the body and are transparent. This makes it relatively easy to study the interaction between neurons and immune cells. Zebrafish are also an excellent animal model for drug discovery. They have already been used for a wide range of other human diseases (including liver, heart and clotting disorders) to elucidate how genes first identified in genome-wide association studies contribute to these disorders. We and others have already been using zebrafish to study familial PD genes. We now want to use our expertise and the major advantages of zebrafish as a model for human diseases to study the PD GWA genes to better understand how they contribute to the risk of sporadic PD. Using a revolutionary new gene editing strategy called 'CRISPR/Cas', we have already made a range of zebrafish lines which carry mutations in 10 of the most important PD GWA risk genes. This pilot work will greatly accelerate the progress of our proposed research. As part of this, we will be studying the effect of these PD GWA risk genes on so-called 'global gene expression'. This involves quantifying how much the brain is using all of the genes in the genome and thereby getting an insight into which biological systems are over or under active. We will also investigate whether PD GWA risk genes interact with familial PD genes. Our work will have a strong focus on the identification of "druggable" targets within these systems. In the future, we are planning to undertake a drug screen against these targets. This will hopefully help us to identify promising drugs which can then be taken into clinical trials for patients with PD.

帕金森病（PD）是一种常见且持续进展的脑部疾病。它的主要症状是运动缓慢，这是由神经细胞（神经元）死亡引起的，这些细胞在大脑的黑质中产生一种叫做多巴胺的化学物质。目前可用的治疗方法是不充分的：首先，它们只能治疗疾病的部分症状，而不是全部症状。其次，它们不能改变潜在的疾病过程，因此不能减缓疾病进展。这种失败部分是由于我们对导致PD的机制的知识有限。在过去的20年中，由于基因缺陷（突变）而导致PD（家族性PD）遗传的基因和机制的鉴定取得了巨大进展。然而，在英国，只有大约5-10%的PD患者携带这种家族性PD突变。该项目旨在阐明遗传因素如何导致更常见的散发性帕金森病的风险。所谓的全基因组关联研究（GWAS）现在已经在我们的基因组中确定了24个区域，这些区域包含导致散发性帕金森病风险的基因。然而，目前尚不清楚这些基因是如何导致帕金森病风险的，在某些情况下，这一区域内的哪个特定基因是负责任的。我们的目标是研究那些最有可能导致PD风险的基因（从这里称为PD GWA基因）。我们和其他人认为，这些基因将参与3种不同的机制，即：1)被称为线粒体的细胞成分对能量产生和能量维持（稳态）的调节。通过称为自噬的过程和称为溶酶体的细胞成分，蛋白质的聚集和分解。3)炎症（细胞对损伤和感染的反应）。我们建议使用携带基因缺陷的斑马鱼来灭活这些PD - GWA基因。斑马鱼是脊椎动物，因此与其他低等动物（如蠕虫或果蝇）相比，与人类的关系要密切得多。它们也为研究PD - GWA基因与衰老过程的相互作用提供了机会。这一点很重要，因为衰老是帕金森病最重要的风险因素。斑马鱼的幼虫在体外发育，是透明的。这使得研究神经元和免疫细胞之间的相互作用相对容易。斑马鱼也是一种很好的药物发现动物模型。它们已经被广泛用于其他人类疾病（包括肝脏、心脏和凝血障碍），以阐明在全基因组关联研究中首次发现的基因如何导致这些疾病。我们和其他人已经在用斑马鱼来研究家族性帕金森病基因。我们现在想利用我们的专业知识和斑马鱼作为人类疾病模型的主要优势来研究PD GWA基因，以更好地了解它们如何导致散发性PD的风险。使用一种革命性的新基因编辑策略“CRISPR/Cas”，我们已经制作了一系列斑马鱼系，这些斑马鱼系携带10种最重要的PD - GWA风险基因突变。这项试点工作将大大加快我们拟议研究的进展。作为其中的一部分，我们将研究这些PD - GWA风险基因对所谓的“全局基因表达”的影响。这包括量化大脑使用基因组中所有基因的程度，从而了解哪些生物系统过度活跃或不活跃。我们还将研究PD GWA风险基因是否与家族性PD基因相互作用。我们的工作将着重于确定这些系统中的“可药物”靶点。未来，我们计划针对这些靶点进行药物筛选。这将有望帮助我们确定有希望的药物，然后将其用于PD患者的临床试验。

项目成果

PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons.

• DOI: 10.1038/s41598-021-84278-7
• 发表时间: 2021-03-23
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Brown SJ;Boussaad I;Jarazo J;Fitzgerald JC;Antony P;Keatinge M;Blechman J;Schwamborn JC;Krüger R;Placzek M;Bandmann O
• 通讯作者: Bandmann O

Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency.

• DOI: 10.1242/dmm.049954
• 发表时间: 2023-06-01
• 期刊: Disease models & mechanisms
• 影响因子: 4.3

The effect of hyperglycemia on neurovascular coupling and cerebrovascular patterning in zebrafish.

• DOI: 10.1177/0271678x18810615
• 发表时间: 2020-02
• 期刊: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
• 作者: Chhabria K;Plant K;Bandmann O;Wilkinson RN;Martin C;Kugler E;Armitage PA;Santoscoy PL;Cunliffe VT;Huisken J;McGown A;Ramesh T;Chico TJ;Howarth C
• 通讯作者: Howarth C

Acid Sphingomyelinase Deficiency Normalizes Neuronal Function in GCase Deficiency - Unexpected Biological Rescue Effect of Combined Genetic Risk Factors for Parkinson's Disease

酸性鞘磷脂酶缺乏使 GCase 缺乏的神经元功能正常化——联合遗传风险因素对帕金森病的意外生物救援作用

• DOI: 10.21203/rs.3.rs-58079/v1
• 发表时间: 2020
• 作者: Keatinge M

Unexpected opposing biological effect of genetic risk factors for Parkinson's disease

帕金森病遗传危险因素的意外相反生物学效应

• DOI: 10.1101/702340
• 发表时间: 2019
• 作者: Keatinge M