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."
Michael C. Purdy | EurekAlert!
Newly designed molecule binds nitrogen
23.02.2018 | Julius-Maximilians-Universität Würzburg
Atomic Design by Water
23.02.2018 | Max-Planck-Institut für Eisenforschung GmbH
A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.
By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...
Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...
For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.
In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.
But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
23.02.2018 | Life Sciences
23.02.2018 | Earth Sciences
23.02.2018 | Materials Sciences