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
Atomic-level motion may drive bacteria's ability to evade immune system defenses
24.04.2017 | Indiana University
Two-dimensional melting of hard spheres experimentally unravelled after 60 years
24.04.2017 | University of Oxford
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
24.04.2017 | Physics and Astronomy
24.04.2017 | Materials Sciences
24.04.2017 | Life Sciences