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Developing a mechanistic rationale for alpha-synuclein targeting therapies in Parkinson's disease

开发帕金森病 α-突触核蛋白靶向疗法的机制原理

基本信息

批准号：
MR/V007068/1
负责人：
George Tofaris
金额：
$ 223.82万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FV007068%2F1
关键词：
Developing mechanistic rationale alpha synuclein

项目摘要

Parkinson's disease is the second most common neurodegenerative disease affecting ~1% of the population over the age of 60. Currently there are only partial symptomatic therapies and no cure. It primarily affects movement and posture due to the death of dopamine producing nerve cells. Mood, memory decline and other difficulties also become prominent as the disease progresses with a significant impact on the quality of patients' and carers' lives. At the molecular level, Parkinson's disease is caused by the accumulation of a small protein called alpha-synuclein and its conversion into clumps called aggregates inside vulnerable neurons. The aggregation of alpha-synuclein causes the death of neurons. Why some types of neurons such as the dopamine producing cells, are more vulnerable to this process of alpha-synuclein aggregation is not fully understood. This may relate to their inability to clear aggregates, counteract their damaging effects or communicate with other types of resident brain cells that survey the environment for toxins such as microglia. One of the limitations for progress has been the lack of human models that recapitulate such pathological events. We have used stem cells derived from patients to generate dopamine producing neurons and triggered alpha-synuclein aggregation in a way that mimics aggregates found in Parkinson's brain. Formation of such aggregates inside the human neurons developed over a period of weeks and caused their death. In this model we have observed that removal of alpha-synuclein aggregates is enhanced when microglia, also derived from stem cells are in contact with neurons. Because we can recapitulate in a human model two critical events of the disease (aggregation and nerve cell death), we are ideally positioned to investigate important outstanding questions in Parkinson's research. (i) Can neurons clear aggregates? We have used state of the art genetic tools (CRISPR) to interrogate all relevant pathways in an unbiased fashion. We have identified a factor that tags alpha-synuclein aggregates for destruction and we will determine how this occurs inside nerve cells. We will employ light-sensitive tags in living neurons to fully understand how the destruction of alpha-synuclein in neurons changes when it is converted from non-aggregated to an aggregated form. (ii) Are neurons with aggregates influenced by external signals from other brain cells? In the brain, neurons respond to or process aggregates in communication with surrounding cells such as microglia. How such signals influence neurons is unclear and complicated by the fact that human microglia often respond differently from what is observed in commonly used mouse models. We will use our human models to understand how microglia promote the removal of aggregates from neurons by testing their ability to "eat up" damaged parts of neurons with aggregates or take up and degrade aggregates released by neurons. We will also analyse which genes are expressed in each microglial cell and neuron individually, to define signals that are responsible for the beneficial interactions we observed. (iii) What makes dopamine producing neurons vulnerable to aggregate-induced death? We will combine our genetic tools (CRISPR) and human models to interrogate factors identified by our gene expression studies. In this way we will identify novel ways to stop the toxic effects of alpha-synuclein aggregation. We will test whether these factors are also detected in Parkinson's brain and are reduced in vulnerable brain regions. Through a multifaceted investigation of a human model of alpha-synuclein aggregation, we aim to understand critical events that cause Parkinson's disease and develop novel therapeutic approaches.

帕金森病是第二大常见的神经退行性疾病，影响约1%的60岁以上人群。目前只有部分对症治疗，没有治愈。它主要影响运动和姿势，因为产生多巴胺的神经细胞死亡。随着疾病的进展，情绪，记忆力下降和其他困难也变得突出，对患者和护理人员的生活质量产生重大影响。在分子水平上，帕金森病是由一种叫做α-突触核蛋白的小蛋白质的积累及其在脆弱神经元内转化为称为聚集体的团块引起的。α-突触核蛋白的聚集导致神经元死亡。为什么某些类型的神经元，如多巴胺产生细胞，更容易受到这种α-突触核蛋白聚集过程的影响，目前还没有完全了解。这可能与它们无法清除聚集体，抵消其破坏性影响或与其他类型的常驻脑细胞沟通有关，这些细胞负责调查环境中的毒素，如小胶质细胞。进展的限制之一是缺乏重现这些病理事件的人类模型。我们已经使用来自患者的干细胞来产生产生多巴胺的神经元，并以模拟帕金森氏症大脑中发现的聚集体的方式触发α-突触核蛋白聚集。在人类神经元内形成这种聚集体需要数周的时间，并导致其死亡。在该模型中，我们观察到，当同样来源于干细胞的小胶质细胞与神经元接触时，α-突触核蛋白聚集体的去除增强。因为我们可以在人类模型中概括疾病的两个关键事件（聚集和神经细胞死亡），我们非常适合调查帕金森研究中重要的悬而未决的问题。(i)神经元能清除聚集体吗？我们使用最先进的遗传工具（CRISPR）以公正的方式询问所有相关途径。我们已经确定了一个标记α-突触核蛋白聚集体的因子，我们将确定这是如何在神经细胞内发生的。我们将在活体神经元中使用光敏标签，以充分了解神经元中α-突触核蛋白的破坏如何从非聚集形式转化为聚集形式。(ii)具有聚集体的神经元会受到来自其他脑细胞的外部信号的影响吗？在大脑中，神经元响应或处理与周围细胞（如小胶质细胞）通信的聚集体。这些信号如何影响神经元尚不清楚，而且由于人类小胶质细胞的反应通常与常用小鼠模型中观察到的不同而变得复杂。我们将使用我们的人类模型来了解小胶质细胞如何通过测试它们“吃掉”具有聚集体的神经元受损部分或吸收和降解神经元释放的聚集体的能力来促进从神经元中去除聚集体。我们还将分析哪些基因在每个小胶质细胞和神经元中单独表达，以定义负责我们观察到的有益相互作用的信号。(iii)是什么使多巴胺产生神经元容易受到聚集诱导的死亡？我们将联合收割机结合我们的遗传工具（CRISPR）和人类模型来询问我们的基因表达研究所确定的因素。通过这种方式，我们将确定新的方法来阻止α-突触核蛋白聚集的毒性作用。我们将测试这些因素是否也在帕金森氏症的大脑中检测到，并在脆弱的大脑区域减少。通过对α-突触核蛋白聚集的人类模型的多方面研究，我们的目标是了解导致帕金森病的关键事件并开发新的治疗方法。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Longitudinal changes of early motor and cognitive symptoms in progressive supranuclear palsy: the OxQUIP study.

DOI：
10.1136/bmjno-2021-000214
发表时间：
2022
期刊：
BMJ neurology open
影响因子：
2.7
作者：
Pereira MF;Buchanan T;Höglinger GU;Bogdanovic M;Tofaris G;Prangnell S;Sarangmat N;FitzGerald JJ;Antoniades CA
通讯作者：
Antoniades CA

Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy

杂合的 UCHL1 功能丧失变异会导致神经退行性疾病，伴有痉挛、共济失调、神经病变和视神经萎缩