Researchers at Johns Hopkins have discovered in mice a molecular wrecking ball that powers the demolition phase of a cycle that occurs at synapses — those specialized connections between nerve cells in the brain — and whose activity appears critical for both limiting and enhancing learning and memory.
The newly revealed protein, which the researchers named thorase after Thor, the Norse god of thunder, belongs to a large family of enzymes that energize not only neurological construction jobs but also deconstruction projects. The discovery is described in the April 15 issue of Cell.
“Thorase is vital for keeping in balance the molecular construction-deconstruction cycle we believe is required for memory formation,” explains Valina Dawson, professor of neurology and neuroscience in the Johns Hopkins Institute of Cell Engineering. “It’s a highly druggable target, which, depending on whether you enhance or inactivate it, may potentially result in new treatments for autism, PTSD, and memory dysfunction.”
The enzyme is one of many AAA+ ATPases that drive the assembly of proteins needed to form specialized receptors at the surfaces of synapses. These receptors are stimulated by neighboring neurons, setting up the signaling and answering connections vital to brain function. The Hopkins team showed how thorase regulates the all-important complementary process of receptor disassembly at synapses, which ultimately tamps down signaling.
Prolonged excitation or inhibition of these receptors — due to injury, disease, genetic malfunction or drugs — has been implicated in a wide array of learning and memory disorders. “Change in the strength of the connections between two nerve cells forms the basis of our ability to learn and remember,” Dawson says. This phenomenon, called synaptic plasticity, depends upon a balanced alternation of excitation and inhibition of receptors, she adds.Using a powerful microscope to look at labeled neurons from the brains of mice, the scientists saw that thorase was concentrated in the synaptic regions of cells, leading them to focus studies on the protein interactions that happen there.
First, they cut a protein aptly called GRIP1 — it acts as scaffolding to hold GluR2 receptors to the surface — into various chunks and combined it with thorase. Encouraged by the fact that thorase and the GRIP1 scaffold did indeed bind tightly, they teased out the physiology of that interaction in the presence of lots of thorase and then no thorase.
They discovered that the more thorase, the quicker the scaffolding deconstructed and the faster the surface receptors decreased. Thorase causes GluR2 receptors and GRIP1 to release their hold on each other, and therefore the receptor’s grip at the surface of the synapse, they concluded.
To see if the deconstruction of the protein complex had any effect on nerve-signaling processes, they again used cells to record receptor activity by measuring electric currents as they fluxed through cells with and without thorase. In the presence of extra thorase, surface receptor expression was decreased, resulting in reduced signaling.
Next, the team measured the rates of receptor recycling by tagging the protein complex with a fluorescent marker. It could then be tracked as it was subsequently reinserted back into the surface membrane of a cell. In cells in which thorase was knocked out, there was very little deconstruction/turnover compared to normal cells. The scientists reversed the process by adding back thorase.
Finally, the team conducted a series of memory tasks in order to compare the behaviors of normal mice with those genetically modified to lack thorase. When the animals lacking thorase were put into a simple maze, their behaviors revealed they had severe deficits in learning and memory.
“Mice lacking thorase appear to stay in a constant state of stimulation, which prevents memory formation,” Dawson explains. “Their receptors get up to the membrane where they are stimulated, but they aren’t being recycled if thorase isn’t present. If thorase doesn’t stop the excitation by recycling the receptor, it continues on and has deleterious effects.”
Support for this research came from the National Institute for Aging and the Intramural Research Program of the National Institute on Aging, McKnight Endowment for Neuroscience, American Heart Association and the Simon’s Foundation Autism Research Initiative.
Authors of the paper, in addition to Valina Dawson, are Jianmin Zhang, Yue Wang, Zhikai Chi, Matthew J. Keuss, Ying-Min Emily Pai, Ho Chul Kang, Jooho Shin, Artem Bugayenko, Hong Wang, Yulan Xiong, Mikhail V. Pletnikov, Mark P. Mattson, and Ted M. Dawson, all of Johns Hopkins.On the Web:
Maryalice Yakutchik | Newswise Science News
New gene catalog of ocean microbiome reveals surprises
18.08.2017 | University of Hawaii at Manoa
Organ Crosstalk: Fatty Liver Can Cause Damage to Other Organs
18.08.2017 | Deutsches Zentrum für Diabetesforschung
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
18.08.2017 | Life Sciences
18.08.2017 | Physics and Astronomy
18.08.2017 | Information Technology