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细胞内膜网膜中的蛋白质保留可以挽救多索菲拉菌中的Aβ毒性

James H Catterson¹, Lucy Minkley², Salomé Aspe²

¹Institute of Healthy Ageing, Genetics, Evolution and Environment, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK; Centre for Discovery Brain Sciences, UK Dementia Research Institute, The University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, Scotland, UK.

Neurobiology of aging

|October 14, 2023

概括

在和小鼠中,在内分泌网膜 (ER) 中过度表达某些蛋白质令人惊地防止与阿尔茨海默病相关的粉样β (Aβ) 毒性,揭示了一种新的治疗策略.

科学领域:

神经科学是一个神经科学.
细胞生物学细胞生物学
遗传学是一个遗传学.

背景情况:

粉样β (Aβ) 积累是阿尔茨海默病 (AD) 的一个关键特征.
Aβ神经毒性的确切机制,无论是内在的还是通过下游途径介导的,仍然不清楚.
人类Aβ在Drosophila大脑中的过度表达会损害运动功能并缩短寿命.

研究的目的:

研究一种新型的防护机制,以防止Aβ毒性.
探索细胞内膜网膜 (ER) 内蛋白质积聚在缓解Aβ诱导的神经退行症中的作用.
确定ER蛋白保留是否可以作为阿尔茨海默病的治疗策略.

主要方法:

在成年Drosophila中,人类Aβ的过度表达.
在Drosophila中过度表达拉米宁子单元 (LanB1) 和原IV的基因操纵.
混焦成像测定蛋白质定位和Aβ水平.
对IRE1α/XBP1 ER应激通路的分析.
在小鼠海马皮切片中进行的原理证明实验,使用小鼠Lamb1的lentiviral输送.

主要成果:

尽管Aβ水平很高,但拉敏B1 (LanB1) 的过度表达显著抵消了Drosophila的Aβ毒性.
其他胺子单元和IV原也表现出保护作用,联合过度表达显示了增强的益处.
兰B1被保留在ER内,而不会影响Aβ分泌.
兰B1的保护作用独立于IRE1α/XBP1 ER应激通路.
针对ER的GFP过度表达也减轻了Aβ毒性,这表明ER蛋白保留的一般好处.
鼠标Lamb1在小鼠海马细胞中显示了ER保留,这表明了一个保存的机制.

结论:

内部ER蛋白质的积累,特别是氨酸和原子单元的积累,提供了一种新的保护机制,可以防止β粉样蛋白毒性.
矛盾的是,ER蛋白保留可以抵消神经元Aβ毒性,为阿尔茨海默病提供潜在的治疗途径.
这种在Drosophila和小鼠模型中保存的机制突显了它的翻译潜力.

关键词:

阿尔茨海默氏症是阿尔茨海默氏症的一种疾病.在Aβ毒性的毒性.这种植物是Drosophila melanogaster.保持ER的保留时间细胞内膜网膜是什么细胞内膜网膜拉米尼尼的拉米尼尼.

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