Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Nat Commun. 2017 Nov 13;8(1):1472. doi: 10.1038/s41467-017-01799-4.
Endoplasmic-reticulum-associated degradation (ERAD) is an important protein quality control system which maintains protein homeostasis. Constituents of the ERAD complex and its role in neurodegeneration are not yet fully understood. Here, using proteomic and FRET analyses, we demonstrate that the ER protein membralin is an ERAD component, which mediates degradation of ER luminal and membrane substrates. Interestingly, we identify nicastrin, a key component of the γ-secretase complex, as a membralin binding protein and membralin-associated ERAD substrate. We demonstrate a reduction of membralin mRNA and protein levels in Alzheimer's disease (AD) brain, the latter of which inversely correlates with nicastrin abundance. Furthermore, membralin deficiency enhances γ-secretase activity and neuronal degeneration. In a mouse AD model, downregulating membralin results in β-amyloid pathology, neuronal death, and exacerbates synaptic/memory deficits. Our results identify membralin as an ERAD component and demonstrate a critical role for ERAD in AD pathogenesis.
内质网相关降解 (ERAD) 是一种重要的蛋白质质量控制系统，可维持蛋白质的内稳态。ERAD 复合物的组成成分及其在神经退行性变中的作用尚不完全清楚。在这里，我们使用蛋白质组学和 FRET 分析表明，内质网蛋白膜联蛋白是 ERAD 的一个组成部分，可介导内质网腔和膜基质的降解。有趣的是，我们鉴定出γ-分泌酶复合物的关键组成部分——尼卡斯特林是膜联蛋白的结合蛋白和膜联蛋白相关的 ERAD 底物。我们发现阿尔茨海默病 (AD) 大脑中的膜联蛋白 mRNA 和蛋白水平降低，后者与尼卡斯特林的丰度呈负相关。此外，膜联蛋白缺失会增强γ-分泌酶的活性并导致神经元变性。在 AD 小鼠模型中，下调膜联蛋白会导致β-淀粉样蛋白病理、神经元死亡，并加剧突触/记忆缺陷。我们的结果确定了膜联蛋白是 ERAD 的一个组成部分，并证明了 ERAD 在 AD 发病机制中的关键作用。
