阿尔茨海默病与泛素-蛋白酶体系统

Alzheimer's disease meets the ubiquitin-proteasome system.

作者信息

Song Sungmin, Jung Yong-Keun

机构信息

Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.

出版信息

Trends Mol Med. 2004 Nov;10(11):565-70. doi: 10.1016/j.molmed.2004.09.005.

DOI:10.1016/j.molmed.2004.09.005

PMID:15519283

Abstract

Ubiquitin-positive deposits are histopathologically found in patients with Alzheimer's disease (AD). It is not understood why ubiquitin is accumulated in intra- and extra-cellular deposits or how it is involved in AD pathogenesis. Interestingly, recent evidence, including studies of E2-25K/Hip-2, has elucidated the molecular mechanism of the ubiquitin-proteasome system (UPS) malfunction in AD. The neurotoxicity and proteasome inhibition by Abeta, a main cause of AD pathogenesis, are mediated by increased E2-25K/Hip-2 in the brains of patients with AD. Furthermore, E2-25K/Hip-2 is required for the neurotoxicity that is mediated by a ubiquitin B mutant (UBB+1), which is a potent inhibitor of proteasomes that is found in patients with AD. Intensive research is required to identify the components of the UPS that are involved in AD pathogenesis.

摘要

在阿尔茨海默病（AD）患者中，组织病理学检查发现存在泛素阳性沉积物。目前尚不清楚泛素为何会在细胞内和细胞外沉积物中积累，以及它如何参与AD的发病机制。有趣的是，最近的证据，包括对E2-25K/Hip-2的研究，阐明了AD中泛素-蛋白酶体系统（UPS）功能障碍的分子机制。AD发病机制的主要原因β淀粉样蛋白（Aβ）的神经毒性和蛋白酶体抑制作用，是由AD患者大脑中E2-25K/Hip-2的增加介导的。此外，泛素B突变体（UBB+1）介导的神经毒性需要E2-25K/Hip-2，UBB+1是在AD患者中发现的一种有效的蛋白酶体抑制剂。需要深入研究以确定参与AD发病机制的UPS成分。