AIMS:Among the putative mechanisms proposed to be common factors in Down syndrome (DS) and Alzheimer's disease (AD) neuropathology, deficits in protein quality control (PQC) have emerged as a unifying mechanism of neurodegeneration. Considering that disturbance of protein degradation systems is present in DS and that oxidized/misfolded proteins require polyubiquitinylation for degradation via the ubiquitin proteasome system, this study investigated if dysregulation of protein polyubiquitinylation is associated with AD neurodegeneration in DS. RESULTS:Postmortem brains from DS cases before and after development of AD neuropathology and age-matched controls were analyzed. By selectively isolating polyubiquitinated proteins, we were able to identify specific proteins with an altered pattern of polyubiquitinylation as a function of age. Interestingly, we found that oxidation is coupled with polyubiquitinylation for most proteins mainly involved in PQC and energy metabolism. INNOVATION:This is the first study showing alteration of the polyubiquitinylation profile as a function of aging in DS brain compared with healthy controls. Understanding the onset of the altered ubiquitome profile in DS brain may contribute to identification of key molecular regulators of age-associated cognitive decline. CONCLUSIONS:Disturbance of the polyubiquitinylation machinery may be a key feature of aging and neurodegeneration. In DS, age-associated deficits of the proteolytic system may further exacerbate the accumulation of oxidized/misfolded/polyubiquitinated proteins, which is not efficiently degraded and may become harmful to neurons and contribute to AD neuropathology. Antioxid. Redox Signal. 26, 280-298.

译文

目的:在被认为是唐氏综合症(DS)和阿尔茨海默氏病(AD)神经病理学的常见因素的推测机制中,蛋白质质量控​​制(PQC)的缺陷已成为神经退行性变的统一机制。考虑到DS中存在蛋白质降解系统的紊乱,并且氧化/错折叠的蛋白质需要通过泛素蛋白酶体系统降解才能进行多泛素化,因此本研究调查了蛋白质多泛素化的失调是否与DS中的AD神经变性有关。
结果:分析了AD患者在AD神经病理学发展之前和之后以及年龄匹配的对照组的死后大脑。通过选择性分离多聚泛素化蛋白,我们能够鉴定出随年龄变化而改变的多聚泛素化模式的特定蛋白。有趣的是,我们发现对于大多数主要参与PQC和能量代谢的蛋白质,氧化与聚泛素化作用有关。
创新:这是第一项研究,表明与健康对照组相比,DS大脑中多泛素化的变化与衰老有关。了解DS脑中遍在基因组谱改变的发作可能有助于识别与年龄相关的认知功能下降的关键分子调节剂。
结论:泛泛素化机制的紊乱可能是衰老和神经退行性变的关键特征。在DS中,与年龄相关的蛋白水解系统缺陷可能会进一步加剧氧化/错折叠/多泛素化蛋白的积累,这种蛋白不能有效降解并且可能对神经元有害并有助于AD神经病理学。抗氧化。氧化还原信号。 26,280-298。

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