Membralin Protein Discovered to be Crucial in Alzheimer’s Pathogenesis
Membralin, a protein, is key to keeping Alzheimer’s disease pathology in check, scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have shown.
Their study shows that membralin regulates the cell’s machinery for producing amyloid beta, the protein that causes neurons to die in Alzheimer’s disease.
“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 membrane, or identify its role in the cellular protein disposal machinery known as the endoplasmic reticulum-associated degradation (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. Xu’s team found that one of the fully formed, working proteins that ERAD regulates is a component of an enzyme called gamma secretase that generates Aβ.
Memory loss in Alzheimer’s results from the toxic effects of Aβ, which causes connections between neurons to break down. Aβ is created when gamma-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 mean that not everyone develops dementia.Using proteomics, microscopic analysis, and functional assays, the group provided definitive evidence that membralin functions as part of the ERAD system.
Later, they found that membralin-dependent ERAD breaks down a protein that’s part of the gamma-secretase enzyme complex, and that reducing the amount of membralin in a mouse model of Alzheimer’s exacerbates neurodegeneration and memory problems.
The team additionally 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.
As previous studies had suggested that ERAD contributes to cells becoming overwhelmed by an irregular accumulation of proteins, including Alzheimer’s, this one, in particular, provides conclusive, mechanistic evidence that ERAD plays an important role in restraining Alzheimer’s disease pathology.
Xu and team further 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.
