UCLA study discovers potassium boost improves walking in mouse model
Tweaking a specific cell type's ability to absorb potassium in the brain improved walking and prolonged survival in a mouse model of Huntington's disease, reports a UCLA study published March 30 in the online edition of Nature Neuroscience. The discovery could point to new drug targets for treating the devastating disease, which strikes one in every 20,000 Americans.
Huntington's disease is passed from parent to child through a mutation in the huntingtin gene. By killing brain cells called neurons, the progressive disorder gradually deprives patients of their ability to walk, speak, swallow, breathe and think clearly. No cure exists, and patients with aggressive cases can die in as little as 10 years.
The laboratories of Baljit Khakh, a professor of physiology and neurobiology, and Michael Sofroniew, a professor of neurobiology, teamed up at the David Geffen School of Medicine at UCLA to unravel the role played in Huntington's by astrocytes--large, star-shaped cells found in the brain and spinal cord.
"Astrocytes appear in the brain in equal numbers to neurons, yet haven't been closely studied. They enable neurons to signal each other by maintaining an optimal chemical environment outside the cells," explained Khakh, who, with Sofroniew, is a member of the UCLA Brain Research Institute. "We used two mouse models to explore whether astrocytes behave differently during Huntington's disease."
The first model mimicked aggressive, early-onset of the disorder, while the second imitated a slow-developing version.
Khakh and Sofroniew examined how the huntingtin mutation influenced astrocytes in the brain. In particular, they looked at astrocytes' interaction with a type of neuron that plays a central role in coordinating movement.
One key finding stood out from the data.
In both models, astrocytes with the mutant gene showed a measurable drop in Kir4.1, a protein that allows the astrocyte to take in potassium through the cell membrane. This left too much potassium outside the cell, disrupting the chemical balance and increasing the nearby neurons' excitability–or capacity to fire.
"We suspect that the gene mutation contributes to Huntington's disease by reducing Kir4.1 levels in the astrocytes," said Sofroniew. "This, in turn, reduces the cell's uptake of potassium.
"When excess potassium pools around neurons, they grow oversensitive and fire too easily, disrupting nerve-cell function and ultimately the body's ability to move properly. This may contribute to the jerky motions common to Huntington's disease," he added.
To test their hypothesis, the scientists explored what would happen if they artificially increased Kir4.1 levels inside the astrocytes. In one example, the results proved striking.
"Boosting Kir4.1 in the astrocytes improved the mice's ability to walk properly. We were surprised to see the length and width of the mouse's stride return to more normal levels," said Khakh. "This was an unexpected discovery."
"Our work breaks new ground by showing that disrupting astrocyte function leads to the disruption of neuron function in a mouse model of Huntington's disease," said Sofroniew. "Our findings suggest that therapeutic targets exist for the disorder beyond neurons."
While the results shed important light on one of the mechanisms behind Huntington's disease, the findings also offer more general implications, according to the authors
"We're really excited that astrocytes can potentially be exploited for new drug treatments," said Khakh. "Astrocyte dysfunction also may be involved in other neurological diseases beyond Huntington's."
The UCLA team's next step will be to tease out the mechanism that reduces Kir4.1 levels and illuminate how this alters neuronal networks.
The study was supported by the CHDI Foundation, the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.
Khakh and Sofroniew's coauthors included Xiaoping Tong, Yan Ao, Guido Faas, Ji Xu, Martin Haustein, Mark Anderson and Istvan Mody from UCLA; and Sinifunanya Nwaobi and Michelle Olsen from the University of Alabama at Birmingham.
Elaine Schmidt | EurekAlert!
Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University
The first analysis of Ewing's sarcoma methyloma opens doors to new treatments
01.12.2016 | IDIBELL-Bellvitge Biomedical Research Institute
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy