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Mitochondrial ubiquitin ligase alleviates Alzheimer’s disease pathology via blocking the toxic amyloid-β oligomer generation
Communications Biology ( IF 5.2 ) Pub Date : 2021-02-12 , DOI: 10.1038/s42003-021-01720-2
Keisuke Takeda 1, 2, 3 , Aoi Uda 1 , Mikihiro Mitsubori 1 , Shun Nagashima 1 , Hiroko Iwasaki 1 , Naoki Ito 1, 4 , Isshin Shiiba 1, 4 , Satoshi Ishido 5 , Masaaki Matsuoka 6 , Ryoko Inatome 1, 4 , Shigeru Yanagi 1, 4
Affiliation  

Mitochondrial pathophysiology is implicated in the development of Alzheimer’s disease (AD). An integrative database of gene dysregulation suggests that the mitochondrial ubiquitin ligase MITOL/MARCH5, a fine-tuner of mitochondrial dynamics and functions, is downregulated in patients with AD. Here, we report that the perturbation of mitochondrial dynamics by MITOL deletion triggers mitochondrial impairments and exacerbates cognitive decline in a mouse model with AD-related Aβ pathology. Notably, MITOL deletion in the brain enhanced the seeding effect of Aβ fibrils, but not the spontaneous formation of Aβ fibrils and plaques, leading to excessive secondary generation of toxic and dispersible Aβ oligomers. Consistent with this, MITOL-deficient mice with Aβ etiology exhibited worsening cognitive decline depending on Aβ oligomers rather than Aβ plaques themselves. Our findings suggest that alteration in mitochondrial morphology might be a key factor in AD due to directing the production of Aβ form, oligomers or plaques, responsible for disease development.



中文翻译:


线粒体泛素连接酶通过阻断有毒的淀粉样蛋白-β寡聚物的生成来缓解阿尔茨海默病的病理学



线粒体病理生理学与阿尔茨海默病 (AD) 的发展有关。基因失调的综合数据库表明,线粒体泛素连接酶 MITOL/MARCH5(线粒体动力学和功能的微调器)在 AD 患者中表达下调。在这里,我们报告说,在患有 AD 相关 Aβ 病理学的小鼠模型中,MITOL 缺失对线粒体动力学的扰动会引发线粒体损伤并加剧认知能力下降。值得注意的是,大脑中 MITOL 缺失增强了 Aβ 原纤维的播种效应,但没有增强 Aβ 原纤维和斑块的自发形成,导致有毒和可分散的 Aβ 寡聚物的二次生成过多。与此一致的是,具有 Aβ 病因的 MITOL 缺陷小鼠表现出认知能力恶化,这取决于 Aβ 寡聚物而不是 Aβ 斑块本身。我们的研究结果表明,线粒体形态的改变可能是 AD 的一个关键因素,因为它指导 Aβ 形式、寡聚体或斑块的产生,从而导致疾病的发展。

更新日期:2021-02-12
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