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

神经退行性疾病包括阿尔茨海默病、帕金森氏病、亨廷顿病、运动神经元病和蛋白病，造成巨大的社会和经济负担。随着人口老龄化，这一负担将急剧增加。目前还没有针对这些疾病的治疗方法，这意味着迫切需要更好地了解其原因并开发治疗方法。我们已经确定了一种名为CHMP2B的新基因，它会导致一种遗传性痴呆症。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，因为这将使我们深入了解许多神经退行性疾病的靶向治疗途径。然而，开发治疗方法的一个主要挑战是了解为什么脑细胞受到特定影响，以便开发出没有副作用的定向治疗方法。为了了解CHMP2B是如何具体影响脑细胞的，我们建立了CHMP2B引起的痴呆的小鼠模型。这些小鼠是一个非常强大的模型，因为它们模拟了人类CHMP2B痴呆症大脑中发生的过程。因此，它们将使我们能够在疾病的非常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。对这些途径的识别应该能深入了解其他神经退行性疾病中脑细胞的脆弱性，并可能找到治疗的新途径。

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.