ER-associated degradation regulates Alzheimer’s amyloid pathology and memory function by modulating γ-secretase activity

• DOI: 10.1038/s41467-017-01799-4
• Publication Date: 2017-11-07T21:57:08Z
• Authors: Bing Zhu; LuLin Jiang; Timothy Huang; Yingjun Zhao; Tongfei Liu; Yongwang Zhong; Xiaoguang Li; Alexandre Campos; Kenneth Pomeroy; Eliezer Masliah; Dongxian Zhang; Huaxi Xu
• Keywords: Endoplasmic-reticulum-associated protein degradation; Nicastrin

Endoplasmic-reticulum-associated degradation (ERAD) is an important protein quality control system which maintains homeostasis. Constituents of the ERAD complex and its role in neurodegeneration are not yet fully understood. Here, using proteomic FRET analyses, we demonstrate that ER membralin component, mediates luminal membrane substrates. Interestingly, identify nicastrin, a key component γ-secretase complex, as binding membralin-associated substrate. We reduction mRNA levels Alzheimer's disease (AD) brain, latter inversely correlates with nicastrin abundance. Furthermore, deficiency enhances activity neuronal degeneration. In mouse AD model, downregulating results β-amyloid pathology, death, exacerbates synaptic/memory deficits. Our critical for pathogenesis.