Well-known enzyme is unexpected contributor to brain growth

March 12, 2009

An enzyme researchers have studied for years because of its potential connections to cancer, diabetes, heart disease, hypertension and stroke, appears to have yet another major role to play: helping create and maintain the brain.

When scientists at Washington University School of Medicine in St. Louis selectively disabled the enzyme AMP-activated protein kinase (AMPK) in mouse embryos, overall brain size was reduced by 50 percent, the cerebrum and cerebellum were shrunken, and the mice died within three weeks of birth.

Researchers showed that the version of AMPK they disabled was essential to the survival of neural stem cells that create the central nervous system. Many scientists believe these same cells also regularly produce new brain cells essential for learning and memory and the general upkeep of the adult brain.

"For years, scientists have showed how AMPK regulates multiple metabolic processes, and revealed how that influence can affect cancer, diabetes, and many other diseases," says senior author Jeffrey Milbrandt, M.D., Ph.D., the David Clayson Professor of Neurology. "Now, for the first time, we've shown that AMPK can cause lasting changes in cell development. That's very exciting because it opens the possibility of modifying AMPK activity to improve brain function and health."

The study was the featured paper in the February issue of Developmental Cell.

AMPK regulates the energy usage of cells and becomes active when energy resources are low, such as during exercise or times of dietary restriction. Activated AMPK inhibits processes that consume energy, like protein synthesis or fatty acid synthesis, and promotes processes that produce energy, such as the oxidation of fatty acids, the uptake of the sugar glucose, or the creation of mitochondria, which are cellular energy-making units. Activated AMPK also suppresses cell reproduction, an ability that scientists have shown can help shut down the proliferation of some cancer cell lines.

The AMPK enzyme is composed of three subunits called alpha, beta and gamma. The human genome contains genes for two to three versions of each subunit. Until now, the beta unit seemed to be "a boring linker" that merely held the three subunits together, according to Milbrandt.

Instead, Milbrandt and Dasgupta found that the beta subunit was determining where AMPK did its job. AMPK with one version of the subunit, beta 1, was found both in the nucleus of cells and in the body of the cell, which is called the cytoplasm. AMPK with beta 2 was never found in the nucleus-just the cytoplasm.

They showed that when activated AMPK gets into the nucleus of stem cells, it inactivates the retinoblastoma protein, a master regulator of cell reproduction. This allows neural stem cells to survive and proliferate.

"Inhibiting AMPK is something that most cells don't like. It can lead to a variety of consequences, including cell death, but many cell types can tolerate it," says lead author Biplab Dasgupta, Ph.D., research instructor in pathology and immunology. "In contrast, neural stem cells undergo catastrophic cell death in the absence of AMPK containing the beta 1 subunit. We also suspect loss of this form of AMPK may cause severe problems for other stem cells."

Dasgupta calls the new finding particularly interesting given previous connections between AMPK and exercise.

"Exercise activates AMPK and improves cognitive function," says Dasgupta. "Our results suggest brain function may improve because additional activated AMPK makes it easier for adult neural stem cells to reproduce and become new brain cells."

Retinoblastoma, the protein regulated by AMPK in the nucleus, also has less well-defined influence on the ability of stem cells to take on specialized characteristics, and this has Milbrandt intrigued about possible connections between AMPK's new role in stem cells and the long-term health effects of malnutrition during pregnancy. A 1977 study of children born to women starved by the Nazis during World War II suggested that the children had increased risk of heart disease, diabetes, stroke and hypertension.

While these are some of the same disorders that have been linked to AMPK activity in adults, those previous links were made through AMPK's role as a manager of cellular energy usage. Milbrandt wonders if changes in AMPK activity triggered by malnutrition could also be affecting stem cell activity in ways that increase long-term health risks in developing infants.

AMPK's role reversal in stem cells calls for careful use of the enzyme in cancer therapy, the researchers note. Recent studies have shown that stem cells can become cancerous, and in those cancers the researchers now believe it might be better to inhibit AMPK than to activate it. Dasgupta will test this hypothesis on cancer stem cell lines.

Milbrandt plans to learn more about how production of different forms of AMPK is regulated.

"Manipulating this regulation may enable us encourage the development of new brain cells," he says. "We might use that not only to treat medical conditions where brain development is hampered but also to improve cognitive function generally."

Washington University School of Medicine

---

---

	Stem Cells For Dummies by Lawrence S.B. Goldstein (Author), Meg Schneider (Author) The first authoritative yet accessible guide to this controversial topicStem Cell Research For Dummies offers a balanced, plain-English look at this politically charged topic, cutting away the hype and presenting the facts clearly for you, free from debate. It explains what stem cells are and what they do, the legalities of harvesting them and using them in research, the latest research findings from the U.S. and abroad, and the prospects for medical stem cell therapies in the short and long term.Explains the differences between adult stem cells and embryonic/umbilical cord stem cellsProvides both sides of the political debate and the pros and cons of each side's opinionsIncludes medical success stories using stem cell therapy and its promise for the futureComprehensive and unbiased, Stem...
	Essentials of Stem Cell Biology, Second Edition by Robert Lanza (Editor), John Gearhart (Editor), Brigid Hogan (Editor), Douglas Melton (Editor), Roger Pederson (Editor), E. Donnall Thomas (Editor), James Thomson (Editor), Sir Ian Wilmut (Editor) First developed as an accessible abridgement of the successful Handbook of Stem Cells, Essentials of Stem Cell Biology serves the needs of the evolving population of scientists, researchers, practitioners and students that are embracing the latest advances in stem cells. Representing the combined effort of seven editors and more than 200 scholars and scientists whose pioneering work has defined our understanding of stem cells, this book combines the prerequisites for a general understanding of adult and embryonic stem cells with a presentation by the world's experts of the latest research information about specific organ systems. From basic biology/mechanisms, early development, ectoderm, mesoderm, endoderm, methods to application of stem cells to specific human diseases, regulation and...
	The Stem Cell Hope: How Stem Cell Medicine Can Change Our Lives by Alice Park (Author) A landmark book by the senior science writer at Time magazine introduces us to a medical breakthrough that can save our lives. Few people know much about stem cell research beyond the ethical questions raised by using embryos. But in the last decade, stem cell research has made huge advances toward eliminating some of our most intractable diseases. Now this sweeping and accessible book introduces us to this cutting-edge science that will revolutionize medicine and change the way we think about and treat disease. Alice Park takes us from stem cell's controversial beginnings to the recent electrifying promise of being able to create the versatile cells without using embryos at all. She shows us how stem cells give researchers an unprecedented ability to study disease while...
	Stem Cells: A Very Short Introduction by Jonathan Slack (Author) Embryonic stem cells have been hot-button topics in recent years, generating intense public interest as well as much confusion and misinformation. In this Very Short Introduction, leading authority Jonathan Slack offers a clear and informative overview of stem cells--what they are, what scientists do with them, what stem cell therapies are available today, and how they might be used in the future. Slack explains the difference between embryonic stem cells, which exist only in laboratory cultures, and tissue-specific stem cells, which exist in our bodies, and he discusses how embryonic stem cells may be used in the future to treat such illnesses as diabetes, Parkinson's disease, heart disease, spinal trauma, and retinal degeneration. But he stresses that, despite important advances, the...
	Stem Cell Now by Christopher Thomas Scott (Author) While many believe stem cell research holds the key to curing a wide range of ailments, others see this research as opening a Pandora’s box that will devalue human life. In Stem Cell Now, Christopher Scott—executive director of Stanford University’s Stem Cells and Society Program—lays out the scientific and ethical issues surrounding this national dilemma. Scott guides readers through the latest advances in stem cell research in clear, accessible language, telling the stories of the researchers who are exploring the potential of stem cells to cure cancer, grow new organs, and repair the immune system. He also leads readers through a discussion of the question at the heart of the explosive ethical debate: How, as a society, do we balance our responsibilities to the unborn and the...
	Stem Cells: Scientific Facts and Fiction by Christine Mummery (Author), Ian Sir Wilmut (Author), Anja Van De Stolpe (Author), Bernard Roelen (Author) In the past decades our understanding of stem cell biology has increased tremendously. Many types of stem cells have been discovered in tissues of which everyone presumed were unable to regenerate in adults; these include particularly the heart and the brain. There is vast interest in stem cells from biologists and clinicians who see the potential for regenerative medicine and future treatments for chronic diseases like Parkinson, diabetes and spinal cord lesions based on the use of stem cells and entrepreneurs in biotechnology who expect new commercial applications ranging from drug discovery to transplantation therapies. As is often the case in science, many early claims turned out to be different from those expected. Embryonic stem cell therapies have not moved rapidly into clinical...
	Human Stem Cell Technology and Biology: A Research Guide and Laboratory Manual by Gary S. Stein (Editor), Maria Borowski (Editor), Mai X. Luong (Editor), Meng-Jiao Shi (Editor), Kelly P. Smith (Editor), Priscilla Vazquez (Editor) Human Stem Cell Technology & Biology: A Research Guide and Laboratory Manual integrates readily accessible text, electronic and video components with the aim of effectively communicating the critical information needed to understand and culture human embryonic stem cells.Key Features:An authoritative, comprehensive, multimedia training manual for stem cell researchersEasy to follow step-by-step laboratory protocols and instructional videos provide a valuable resourceA must-have for developing laboratory course curriculums, training courses, and workshops in stem cell biologyPerspectives written by the world leaders in the fieldIntroductory chapters will provide background informationThe volume will be a valuable reference resource for both experienced investigators pursuing stem cell and...
	Cells That Heal Us From Cradle To Grave: A Quantum Leap in Medical Science Roger M. Nocera, M.D., a world leader in stem cell therapy research, announces a breakthrough medical science discovery that will revolutionize health care as we know it. In his new book "Cells That Heal Us From Cradle To Grave: A Quantum Leap in Medical Science," Dr. Nocera reveals that a medical science discovery made in 2003 has been developed in medical clinics around the world and proven to be effective in the treatment of many heretofore incurable diseases. Cells That Heal Us From Cradle To Grave explains how this medical science discovery is on a par with Immunology discovered two centuries ago with the smallpox vaccine, and with the discovery of antibiotics a century later. Dr. Nocera’s book is a primer on how this amazing new medical...
	Essential Stem Cell Methods (Reliable Lab Solutions) by Robert Lanza (Editor), Irina Klimanskaya (Editor) As part of the Reliable Lab Solutions series, this volume offers an abridged and comprehensive update of selected chapters that first appeared in the three-volume stem cell series published in Methods in Enzymology. Currently, stem cells are of great interest to scientists and clinicians due to their unique ability to differentiate into various tissues of the body, making them a promising source of cells for regenerative medicine and drug discovery as well as an excellent model of vertebrate development. Essential Stem Cell Methods features a detailed set of protocols written by experts in the field and hand-selected by the editors to help researchers drive advances in this fast-moving field. The result is a clear set of step-by-step methods which steer the reader through the...
	Blocked In The USA: The Stem Cell Miracle by Dr William Rader (Author) If you thought the time of dramatic evolutionary advancement in medical knowledge was over, brace yourself for the untold story of a doctor who singlehandedly, in the face of disdain from his colleagues and threats from government bureaucrats, made a breakthrough scientific discovery. Dr. Rader discovered how to apply fetal stem cell technology to humans and has eased the suffering and at times saved the lives of more than 1,500 patients with Autism, Epilepsy, Multiple Sclerosis, Stroke, Parkinson's disease, Muscular Dystrophy, and many other diseases since 1995.Dr. Rader, familiar to millions as a respected medical expert on ABC-TV, reveals the astounding truth about the most extensive fetal stem cell trials ever conducted on human patients - mostly so - called "hopeless" cases. Blocked...