Researchers at the Sanford Burnham Prebys Medical Discovery Institute (SBP) say they have shown that membralin is critical for keeping Alzheimer’s disease pathology in check. The study (“ER-Associated Degradation Regulates Alzheimer’s Amyloid Pathology and Memory Function by Modulating γ-Secretase Activity”), published in Nature Communications, demonstrates that membralin regulates the cell’s machinery for producing amyloid-beta (Aβ), the protein that causes neurons to die in Alzheimer’s disease.
“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,” write the investigators.
“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.”
“Our results suggest a new path toward future treatments for Alzheimer’s disease,” says Huaxi Xu, Ph.D., the Jeanne and Gary Herberger Leadership Chair of SBP’s Neuroscience and Aging Research Center. “If we can find molecules that modulate membralin, or identify its role in the cellular protein disposal machinery known as the ERAD system, this may put the brakes on neurodegeneration.”
Membralin Protein Found Critical in Regulating Amyloid-Beta Production