Investigation of the mechanism of CHMP2B-induced neurodegeneration using a novel transgenic mouse model

使用新型转基因小鼠模型研究 CHMP2B 诱导的神经变性机制

• 批准号: MR/J004022/1
• 负责人: Adrian Isaacs
• 金额: $ 61.62万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ004022%2F1
• 关键词: Investigation; mechanism; CHMP2B; induced; neurodegeneration

The neurodegenerative diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, motor neuron disease and prion diseases cause huge social and economic burden. This burden is set to increase dramatically as the population ages. Currently no therapies are available for these diseases, implying an urgent need to better understand their causes and develop therapies. We have identified a new gene, termed CHMP2B, that causes an inherited form of dementia. We have shown that CHMP2B affects the ability of cells to break down proteins, which is a problem that has been identified in many other neurodegenerative diseases. We therefore plan to further investigate how CHMP2B affects brain cells as this should give insight into pathways that could be targeted therapeutically in many neurodegenerative diseases. However, a major challenge for developing therapies is understanding why brain cells are specifically affected, so that directed therapies without side effects can be developed. In order to understand how CHMP2B specifically affects brain cells, we have generated mice that model dementia caused by CHMP2B. These mice are a very powerful model as they mimic the processes occurring in human CHMP2B dementia brains. They will therefore allow us to specifically examine brain cells at very early stages of the disease in order to identify why they are particularly vulnerable to dysfunction and death. Identification of these pathways should give insight into brain cell vulnerability in other neurodegenerative diseases and could identify new avenues for treatments.

阿尔茨海默病、帕金森病、亨廷顿病、运动神经元病和朊病毒病等神经退行性疾病给人类社会和经济造成了巨大的负担。随着人口老龄化，这一负担将急剧增加。目前没有治疗这些疾病的方法，这意味着迫切需要更好地了解其原因并开发治疗方法。我们已经发现了一种新的基因，称为CHMP2B，它会导致遗传性痴呆。我们已经证明，CHMP2B影响细胞分解蛋白质的能力，这是一个在许多其他神经退行性疾病中已经发现的问题。因此，我们计划进一步研究CHMP2B如何影响脑细胞，因为这应该可以深入了解在许多神经退行性疾病中可以靶向治疗的途径。然而，开发治疗方法的一个主要挑战是了解为什么脑细胞会受到特别影响，以便开发无副作用的定向治疗。为了了解CHMP2B如何特异性地影响脑细胞，我们已经产生了由CHMP2B引起的痴呆模型小鼠。这些小鼠是一个非常强大的模型，因为它们模仿了人类CHMP2B痴呆大脑中发生的过程。因此，它们将使我们能够在疾病的早期阶段专门检查脑细胞，以确定为什么它们特别容易受到功能障碍和死亡的影响。这些通路的识别应该可以深入了解其他神经退行性疾病中的脑细胞脆弱性，并可以确定新的治疗途径。

项目成果

Regulation of Postsynaptic Function by the Dementia-Related ESCRT-III Subunit CHMP2B

• DOI: 10.1523/jneurosci.0586-14.2015
• 发表时间: 2015-02-18
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Chassefeyre, Romain;Martinez-Hernandez, Jose;Goldberg, Yves
• 通讯作者: Goldberg, Yves

C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci.

• DOI: 10.1007/s00401-013-1200-z
• 发表时间: 2013-12
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Mizielinska S;Lashley T;Norona FE;Clayton EL;Ridler CE;Fratta P;Isaacs AM
• 通讯作者: Isaacs AM

In search of lost trafficking

寻找迷失的贩运

• DOI: 10.1093/brain/awy294
• 发表时间: 2018
• 期刊: Brain
• 影响因子: 14.5
• 作者: Bechek S

Conformation determines the seeding potencies of native and recombinant Tau aggregates.

• DOI: 10.1074/jbc.m114.589309
• 发表时间: 2015-01-09
• 期刊: The Journal of biological chemistry
• 作者: Falcon B;Cavallini A;Angers R;Glover S;Murray TK;Barnham L;Jackson S;O'Neill MJ;Isaacs AM;Hutton ML;Szekeres PG;Goedert M;Bose S
• 通讯作者: Bose S

Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown.

• DOI: 10.1093/brain/awy284
• 发表时间: 2018-12-01
• 期刊: Brain : a journal of neurology
• 作者: Clayton EL;Milioto C;Muralidharan B;Norona FE;Edgar JR;Soriano A;Jafar-Nejad P;Rigo F;Collinge J;Isaacs AM
• 通讯作者: Isaacs AM