JPND Pathway complexities of protein misfolding in neurodegenerative diseases: a novel approach to risks evaluation and model development

JPND 神经退行性疾病中蛋白质错误折叠的通路复杂性：风险评估和模型开发的新方法

• 批准号: MC_EX_MR/N027892/1
• 负责人: Michel Goedert
• 金额: $ 14.75万
• 依托单位: MRC Laboratory of Molecular Biology
• 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=MC_EX_MR%2FN027892%2F1
• 关键词: JPND; Pathway; complexities; protein; misfolding

The deposition of misfolded proteins in the central nervous system (CNS) of affected individuals is acommon feature of major neurodegenerative disorders including Alzheimer's disease (AD), Parkinson'sdisease (PD), fronto-temporal dementias and prion diseases. Taken together, these diseases affect ~50million people worldwide. AD, the most common form, is characterized by the cerebral deposition ofaggregated amyloid Beta (ABeta) and tau, while PD is characterized by neuronal inclusions known as Lewybodies that are comprised of the protein alpha-synuclein (alpha-syn). In prion diseases, the aggregated misfoldedprion protein, called prion, is widespread in the CNS. A large body of histopathological, genetic, andexperimental studies clearly implicates the conversion of native proteins into abnormal distinctconformations as a key step in the variegate disease pathogenesis. In this proposal we aim at studyingthe molecular determinants of the so-called strain phenomenon in the different diseases and relate theresults to the functional and clinical outcome using several experimental tools. First, we plan to use smallmolecules to discriminate different structural conformers of ABeta, tau and alpha-syn. These molecules includeluminescent conjugated oligothiophenes. In vitro and in vivo testing in cellular and animal models andhuman autopsy brains from clinically characterized disease cases will parallel biochemical andbiophysical characterizations of such disease-related conformers. In addition, we propose theidentification of genetic/epigenetic risk or protective factors through a high-throughput siRNA andRNSseq screenings for modifiers involved in the pathogenesis of these diseases. These latter twoapproaches will be paralleled by the study of the genes identified through in vitro and in vivo approachesfor the development of novel experimental models for these diseases.The work plan proposed will address the genetic, epigenetic and environmental risk and protective factorsand it will allow the development of novel advanced experimental models of neurodegenerative diseases.

错折叠蛋白在中枢神经系统（CNS）的沉积是阿尔茨海默病（AD）、帕金森病（PD）、额颞叶痴呆和朊病毒病等主要神经退行性疾病的共同特征。总的来说，这些疾病影响着全世界约5000万人。AD是最常见的形式，其特征在于聚集的淀粉样蛋白β（ABeta）和tau的脑沉积，而PD的特征在于由蛋白质α-突触核蛋白（α-syn）组成的称为Lewybodies的神经元包涵体。在朊病毒疾病中，聚集的错误折叠的朊病毒蛋白，称为朊病毒，广泛存在于中枢神经系统中。大量的组织病理学、遗传学和实验研究清楚地表明，天然蛋白质转化为异常的独特构象是杂色病发病机制的关键步骤。在这个建议中，我们的目的是研究不同疾病中所谓应变现象的分子决定因素，并使用几种实验工具将结果与功能和临床结果联系起来。首先，我们计划使用小分子来区分ABeta，tau和alpha-syn的不同结构构象。这些分子包括发光共轭低聚噻吩。在细胞和动物模型中的体外和体内测试以及临床特征疾病病例的人类尸检大脑将平行于这些疾病相关构象的生化和生物物理特征。此外，我们建议通过高通量siRNA和RNSseq筛选参与这些疾病发病机制的修饰剂来鉴定遗传/表观遗传风险或保护因素。后两种方法将通过研究通过体外和体内方法鉴定的基因来开发这些疾病的新实验模型，提出的工作计划将解决遗传，表观遗传和环境风险和保护因素，并将允许开发新的先进的神经退行性疾病实验模型。

项目成果

Galectin-8-mediated selective autophagy protects against seeded tau aggregation.

• DOI: 10.1074/jbc.m117.809293
• 发表时间: 2018-02-16
• 期刊: The Journal of biological chemistry
• 作者: Falcon B;Noad J;McMahon H;Randow F;Goedert M
• 通讯作者: Goedert M

Cryo-EM structures of tau filaments from Alzheimer's disease.

• DOI: 10.1038/nature23002
• 发表时间: 2017-07-13
• 期刊: Nature
• 影响因子: 64.8
• 作者: Fitzpatrick AWP;Falcon B;He S;Murzin AG;Murshudov G;Garringer HJ;Crowther RA;Ghetti B;Goedert M;Scheres SHW
• 通讯作者: Scheres SHW

Structures of α-synuclein filaments from multiple system atrophy

• DOI: 10.1038/s41586-020-2317-6
• 发表时间: 2020-09-17
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Schweighauser, Manuel;Shi, Yang;Goedert, Michel
• 通讯作者: Goedert, Michel

Novel tau filament fold in corticobasal degeneration

• DOI: 10.1038/s41586-020-2043-0
• 发表时间: 2020-02-12
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Zhang, Wenjuan;Tarutani, Airi;Scheres, Sjors H. W.
• 通讯作者: Scheres, Sjors H. W.