New Player in Alzheimer’s Disease Pathogenesis Identified

Scientists at the Sanford Burnham Prebys Medical Discovery Institute (SBP) have shown that a protein called 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, shows 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.”

ERAD is the mechanism by which cells get rid of proteins that are folded incorrectly in the ER. It also controls the levels of certain mature, functional proteins. Dr. Xu’s team found that one of the fully formed working proteins that ERAD regulates is a component of an enzyme called γ-secretase that generates Aβ.

This discovery helps fill in the picture of regarding Alzheimer’s disease, an incredibly complicated disorder influenced by many genetic and environmental factors, according to the researchers. No therapies have yet been demonstrated to slow progression of the disease, which affects around 47 million people worldwide. Until such drugs are developed, patients face a steady, or sometimes rapid, decline in memory and reasoning.

Memory loss in Alzheimer’s results from the toxic effects of Aβ, which causes connections between neurons to break down. Aβ is created when γ-secretase cuts the amyloid precursor protein into smaller pieces. While Aβ is made in all human brains as they age, differences in the rate at which it is produced and eliminated from the brain and in how it affects neurons means that not everyone develops dementia.

“We were interested in membralin because of its genetic association with Alzheimer’s, and in this study we established the connection between membralin and Alzheimer’s based on findings from the laboratory of a former colleague at SBP, Prof. Dongxian Zhang,” Dr. Xu explains. “That investigation showed that eliminating the gene for membralin leads to rapid motor neuron degeneration, but its cellular function wasn’t clear.”

Using proteomics, microscopic analysis, and functional assays, the group provided definitive evidence that membralin functions as part of the ERAD system, continues Dr. Xu. Later, the team found that membralin-dependent ERAD breaks down a protein that’s part of the γ-secretase enzyme complex, and that reducing the amount of membralin in a mouse model of Alzheimer’s exacerbates neurodegeneration and memory problems.

“Our findings explain why mutations that decrease membralin expression would increase the risk for Alzheimer’s,” Dr. Xu comments. “This would lead to an accumulation of γ-secretase because its degradation is disabled, and the γ-secretase complex would then generate more Aβ. Those mutations are rare, but there may be other factors that cause neurons to make less membralin.”

Dr. Xu and colleagues also observed lower levels of membralin, on average, in the brains of patients with Alzheimer’s than in unaffected individuals, demonstrating the relevance of their findings to humans.

“Previous studies have suggested that ERAD contributes to many diseases where cells become overwhelmed by an irregular accumulation of proteins, including Alzheimer’s,” says Dr. Xu. “This study provides conclusive, mechanistic evidence that ERAD plays an important role in restraining Alzheimer’s disease pathology. We now plan to search for compounds that enhance production of membralin or the rate of ERAD to test whether they ameliorate pathology and cognitive decline in models of Alzheimer’s. That would further support the validity of this mechanism as a drug target.”