A well-known enzyme linked with cancer, diabetes, heart disease, hypertension, and stroke has now been found to help create and maintain the brain, according to scientists at Washington University School of Medicine in St. Louis.
After selectively disabling the enzyme AMP-activated protein kinase (AMPK) in mouse embryos, it was found that the overall brain size was reduced by 50 percent, the cerebrum and cerebellum were shrunken, and the mice died within three weeks of birth.
AdvertisementThe scientists showed that the disabled version of AMPK was vital to the survival of neural stem cells that create the central nervous system.
Many scientists believe these 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," said senior author Jeffrey Milbrandt, M.D., Ph.D., the David Clayson Professor of Neurology.
He added: "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 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.
Milbrandt said that, to date, the beta unit was considered to be "a boring linker" that merely held the three subunits together.
But, in the current study, the researchers 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," said lead author Biplab Dasgupta, Ph.D., research instructor in pathology and immunology.
He added: "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."
In his opinion, the new finding is particularly interesting given the previous connections between AMPK and exercise.
"Exercise activates AMPK and improves cognitive function. 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," said Dasgupta.
The study has been featured in the journal Developmental Cell.
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