New player in Alzheimer's disease pathogenesis identifiedNovember 14, 2017
La Jolla, Calif., November 13, 2016 -- Scientists at 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, published in Nature Communications, shows that membralin regulates the cell's machinery for producing beta-amyloid (or amyloid beta, Aβ), 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 membralin, 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.
This discovery helps fill in the picture of how Alzheimer's disease, an incredibly complicated disorder influenced by many genetic and environmental factors. 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 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, 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, Professor Dongxian Zhang," 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. 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.
"Our findings explain why mutations that decrease membralin expression would increase the risk for Alzheimer's," Xu comments. "This would lead to an accumulation of gamma secretase because its degradation is disabled, and the gamma-secretase complex would then generate more Aβ. Those mutations are rare, but there may be other factors that cause neurons to make less membralin."
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 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."
Bing Zhu and Lu-Lin Jiang from SBP were co-first authors on this paper. This research was performed in collaboration with scientists at the University of Maryland School of Medicine, UC San Diego, and Xiamen University.
Funding was provided by the National Institutes of Health, the Tanz Family Fund, and the Cure Alzheimer's Fund.
Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.
Sanford-Burnham Prebys Medical Discovery Institute
Related Neurons Articles:
One of the big challenges in the Neuroscience field is to understand how connections and communications trigger our behavior.
In a new study published in Neuron, investigators report on a transcription factor that they have found that can help certain neurons regenerate, while simultaneously killing others.
When many individual neurons collect data, how do they reach a unanimous decision?
Individual neurons can learn not only single responses to a particular signal, but also a series of reactions at precisely timed intervals.
Putting a turbo engine into an old car gives it an entirely new life -- suddenly it can go further, faster.
Turning the theory of how the human brain perceives time on its head, a novel analysis in mice reveals that dopamine neuron activity plays a key role in judgment of time, slowing down the internal clock.
Researchers have identified a large population of previously unrecognized young neurons that migrate in the human brain during the first few months of life, contributing to the expansion of the frontal lobe, a region important for social behavior and executive function.
For decades, scientists have struggled to develop a comprehensive census of cell types in the brain.
In the brain, patterns of neural activity are perfectly balanced.
University of Alberta researchers have developed a method of connecting neurons, using ultrashort laser pulses -- a breakthrough technique that opens the door to new medical research and treatment opportunities.
Related Neurons Reading:
From Neuron to Brain
by John G. Nicholls (Author), A. Robert Martin (Author), David A. Brown (Author), Mathew E. Diamond (Author), David A. Weisblat (Author), Paul A. Fuchs (Author)
From Neuron to Brain, Fifth Edition, provides a readable, up-to-date book for use in undergraduate, graduate, and medical school courses in neuroscience. As in previous editions, the emphasis is on experiments made by electrical recordings, molecular and cellular biological techniques, and behavioral studies on the nervous system, from simple reflexes to cognitive functions. Lines of research are followed from the inception of an idea to new findings being made in laboratories and clinics today.
A major change is that this edition begins with the anatomy and physiology of the... View Details
The Neuron: Cell and Molecular Biology
by Irwin B. Levitan (Author), Leonard K. Kaczmarek (Author)
The Fourth Edition of The Neuron provides a comprehensive first course in the cell and molecular biology of nerve cells. The book begins with properties of the many newly discovered ion channels that have emerged through mapping of the genome. These channels shape the way a single neuron generates varied patterns of electrical activity. Covered next are the molecular mechanisms that convert electrical activity into the secretion of neurotransmitter hormones at synaptic junctions between neurons. The following section examines the biochemical pathways that are linked to the action of... View Details
The Neuron: Cell and Molecular Biology
by Irwin B. Levitan (Author), Leonard K. Kaczmarek (Author)
The third edition of The Neuron provides a comprehensive first course in the cell and molecular biology of nerve cells. The first part of the book covers the properties of the many ion channels that shape the way a single neuron generates varied patterns of electrical activity, as well as the molecular mechanisms that convert electrical activity into the secretion of neurotransmitter hormones at synaptic junctions between neurons. The second part covers the biochemical pathways that are linked to the action of neurotransmitters and can alter the cellular properties of neurons or... View Details
From Photon to Neuron: Light, Imaging, Vision
by Philip Nelson (Author)
A richly illustrated undergraduate textbook on the physics and biology of light
Students in the physical and life sciences, and in engineering, need to know about the physics and biology of light. Recently, it has become increasingly clear that an understanding of the quantum nature of light is essential, both for the latest imaging technologies and to advance our knowledge of fundamental life processes, such as photosynthesis and human vision. From Photon to Neuron provides undergraduates with an accessible introduction to the physics of light and offers a unified view... View Details
The 7 Secrets of Neuron Leadership: What Top Military Commanders, Neuroscientists, and the Ancient Greeks Teach Us about Inspiring Teams
by W. Craig Reed (Author), Gordon R. England (Foreword)
Leadership techniques backed by the world's most effective teams
The 7 Secrets of Neuron Leadership offers a diverse collection of wisdom and practical knowledge to help you build and lead your most effective team yet. Written by a former U.S. Navy diver, this book draws from the author's experiences and beyond to reveal key truths about the nature of teamwork, and expose the core of effective team leadership. You'll go back to ancient Greece to discover the nine personality types and the seven types of love that form the foundation of human interaction, and learn how... View Details
Neurons In Action 2: Tutorials and Simulations using NEURON
by John W. Moore (Author), Anne E. Stuart (Author)
Neurons in Action 2 is the second version of a unique CD-ROM-based learning tool that combines hyperlinked text with NEURON simulations of laboratory experiments in neurophysiology. Version 2 features nine new tutorials introducing new channel types, single-channel simulations, and a redesigned interface. Neurons in Action s moving graphs provide insight into nerve function that is simply not possible with conventional, static text and figure presentations. Students discover how changing parameters such a neuronal geometry, ion concentrations, ion channel densities, and degree of myelination... View Details
From Neurons to Neighborhoods : The Science of Early Childhood Development
by Committee on Integrating the Science of Early Childhood Development (Author), Youth, and Families Board on Children (Author), National Research Council (Author), Committee on Integrating the Science of Early Childhood Development (Author), Jack P. Shonkoff (Editor), Deborah A. Phillips (Editor)
How we raise young children is one of today's most highly personalized and sharply politicized issues, in part because each of us can claim some level of "expertise." The debate has intensified as discoveries about our development-in the womb and in the first months and years-have reached the popular media.
How can we use our burgeoning knowledge to assure the well-being of all young children, for their own sake as well as for the sake of our nation? Drawing from new findings, this book presents important conclusions about nature-versus-nurture, the impact of being born into a... View Details
From Neuron to Cognition via Computational Neuroscience (Computational Neuroscience Series)
by Michael A. Arbib (Editor), James J. Bonaiuto (Editor)
A comprehensive, integrated, and accessible textbook presenting core neuroscientific topics from a computational perspective, tracing a path from cells and circuits to behavior and cognition.
This textbook presents a wide range of subjects in neuroscience from a computational perspective. It offers a comprehensive, integrated introduction to core topics, using computational tools to trace a path from neurons and circuits to behavior and cognition. Moreover, the chapters show how computational neuroscience -- methods for modeling the causal interactions underlying neural... View Details
The Myth of Mirror Neurons: The Real Neuroscience of Communication and Cognition
by Gregory Hickok (Author)
An essential reconsideration of one of the most far-reaching theories in modern neuroscience and psychology.In 1992, a group of neuroscientists from Parma, Italy, reported a new class of brain cells discovered in the motor cortex of the macaque monkey. These cells, later dubbed mirror neurons, responded equally well during the monkey’s own motor actions, such as grabbing an object, and while the monkey watched someone else perform similar motor actions. Researchers speculated that the neurons allowed the monkey to understand others by simulating their actions in its... View Details
I of the Vortex: From Neurons to Self
by Rodolfo R. Llinas (Author)
A highly original theory of how the mind-brain works, based on the author's study of single neuronal cells.
In I of the Vortex, Rodolfo Llinas, a founding father of modern brain science, presents an original view of the evolution and nature of mind. According to Llinas, the "mindness state" evolved to allow predictive interactions between mobile creatures and their environment. He illustrates the early evolution of mind through a primitive animal called the "sea squirt." The mobile larval form has a brainlike ganglion that receives sensory information about the... View Details