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

Bing Zhu, LuLin Jiang, Timothy Huang, Yingjun Zhao, Tongfei Liu, Yongwang Zhong, Xiaoguang Li, Alexandre Campos, Kenneth Pomeroy, Eliezer Masliah, Dongxian Zhang and Huaxi Xu ()
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Bing Zhu: Sanford Burnham Prebys Medical Discovery Institute
LuLin Jiang: Sanford Burnham Prebys Medical Discovery Institute
Timothy Huang: Sanford Burnham Prebys Medical Discovery Institute
Yingjun Zhao: Sanford Burnham Prebys Medical Discovery Institute
Tongfei Liu: Sanford Burnham Prebys Medical Discovery Institute
Yongwang Zhong: University of Maryland School of Medicine
Xiaoguang Li: Sanford Burnham Prebys Medical Discovery Institute
Alexandre Campos: Sanford Burnham Prebys Medical Discovery Institute
Kenneth Pomeroy: Sanford Burnham Prebys Medical Discovery Institute
Eliezer Masliah: University of California, San Diego
Dongxian Zhang: Sanford Burnham Prebys Medical Discovery Institute
Huaxi Xu: Sanford Burnham Prebys Medical Discovery Institute

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01799-4

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