Protection of neurons in vitro and in vivo from Synuclein toxicity by molecular tweezers

通过分子镊子保护体外和体内神经元免受突触核蛋白毒性

• 批准号: MR/P007058/1
• 负责人: Richard Wade-Martins
• 金额: $ 18.5万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP007058%2F1
• 关键词: Protection; neurons; vitro; vivo; Synuclein

Parkinson's disease is an age-related neurodegenerative disorder in which aggregated clumps of a protein termed alpha-synuclein form in neurons, the cells in the brain which relay electrical information. These clumps are the defining key hallmark pathology of Parkinson's and are called Lewy bodies (LB). In a related disease, multiple system atrophy (MSA), the protein clumps form in the support cells, called glia. The diseases are therefore related and may benefit from a therapy to prevent the formation and spread of alpha-synuclein protein clumps. The development of therapeutic strategies to prevent the formation and spread of alpha-synuclein protein clumps and prevent cell death in Parkinson's and MSA has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence demonstrates the importance of the alpha-synuclein clumps in disease pathology and has led to consider the therapeutic potential of several strategies aimed at reducing the burden and toxicity of alpha-synuclein accumulation. Our objective here is to build upon the unique experimental models of disease and complementary expertise of the Consortium. Members of the research team specialise in working in brain cells from mice, and with human neurons derived from stem cells made from Parkinson's patients. Others members of the team work on animal models of Parkinson's and MSA which model how alpha-synuclein may spread in the brain. We will use these models in laboratories in France and in the UK to test a novel molecular therapy called "molecular tweezer" drug which has been shown to inhibit aggregation and toxicity of other similar proteins which clump in other diseases. The drug may therefore protect neurons grown in the laboratory and neurons in the brain from Parkinson's or MSA-associated cell death. By probing the mechanisms and application of "molecular tweezers" to Parkinson's and MSA the project will demonstrate the use or not of such a therapy to prevent alpha-synuclein-mediated cell death.

帕金森氏病是一种与年龄相关的神经退行性疾病，其中称为α-突触核蛋白的蛋白质聚集在神经元中形成，神经元是大脑中传递电信息的细胞。这些团块是帕金森病的关键病理标志，被称为路易体（LB）。在一种相关的疾病中，多系统萎缩（MSA），蛋白质团块在称为神经胶质的支持细胞中形成。因此，这些疾病是相关的，并且可能受益于预防α-突触核蛋白蛋白团块形成和扩散的疗法。由于缺乏对驱动神经变性的机制的理解，在帕金森病和MSA中预防α-突触核蛋白蛋白团块的形成和扩散以及预防细胞死亡的治疗策略的开发受到限制。然而，越来越多的证据表明α-突触核蛋白团块在疾病病理学中的重要性，并导致考虑旨在减少α-突触核蛋白积累的负担和毒性的几种策略的治疗潜力。我们的目标是建立在独特的疾病实验模型和该联盟的互补专业知识的基础上。该研究小组的成员专门从事小鼠脑细胞的研究，以及从帕金森患者的干细胞中提取的人类神经元。该团队的其他成员研究帕金森病和MSA的动物模型，这些模型模拟了α-突触核蛋白如何在大脑中传播。我们将在法国和英国的实验室中使用这些模型来测试一种名为“分子镊子”的新型分子疗法药物，该药物已被证明可以抑制其他疾病中聚集的其他类似蛋白质的聚集和毒性。因此，这种药物可以保护实验室中生长的神经元和大脑中的神经元免受帕金森病或MSA相关细胞死亡的影响。通过探索帕金森病和MSA的“分子镊子”的机制和应用，该项目将证明使用或不使用这种疗法来防止α-突触核蛋白介导的细胞死亡。

项目成果

Alpha-synuclein oligomers: a new hope.

• DOI: 10.1007/s00401-017-1755-1
• 发表时间: 2017-12
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Bengoa-Vergniory N;Roberts RF;Wade-Martins R;Alegre-Abarrategui J
• 通讯作者: Alegre-Abarrategui J

CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease.

• DOI: 10.1038/s41467-020-18689-x
• 发表时间: 2020-09-28
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Bengoa-Vergniory N;Faggiani E;Ramos-Gonzalez P;Kirkiz E;Connor-Robson N;Brown LV;Siddique I;Li Z;Vingill S;Cioroch M;Cavaliere F;Threlfell S;Roberts B;Schrader T;Klärner FG;Cragg S;Dehay B;Bitan G;Matute C;Bezard E;Wade-Martins R
• 通讯作者: Wade-Martins R

Tau-proximity ligation assay reveals extensive previously undetected pathology prior to neurofibrillary tangles in preclinical Alzheimer's disease.

• DOI: 10.1186/s40478-020-01117-y
• 发表时间: 2021-01-28
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Bengoa-Vergniory N;Velentza-Almpani E;Silva AM;Scott C;Vargas-Caballero M;Sastre M;Wade-Martins R;Alegre-Abarrategui J
• 通讯作者: Alegre-Abarrategui J

The stem cell cocktail: neural reprogramming just got easier.

干细胞鸡尾酒：神经重新编程变得更容易。

• DOI: 10.21037/sci.2016.09.11
• 发表时间: 2016
• 期刊: Stem cell investigation
• 作者: Bengoa-Vergniory N