In a series of experiments reported today (Dec. 9) in the Journal of Neuroscience, a University of Wisconsin-Madison pharmacy researcher was able to prolong life and slow nerve deterioration in a mouse with a genetic form of ALS. Marcelo Vargas, a postdoctoral fellow in the laboratory of Jeff Johnson, a professor in the School of Pharmacy, tested mice that carried an extra gene that pushed support cells for the neurons into overdrive, causing them to pump out extra quantities of the antioxidant glutathione.
The gene in question, called Nrf2, has long been a research focus for Johnson, who is also an investigator at UW-Madison’s Waisman Center.
Although oxidation is a major cause of cell death in Parkinson’s disease and Alzheimer’s disease as well as ALS, antioxidant treatments have failed to slow these diseases.
But the mice with extra copies of Nrf2 produced glutathione right alongside the vulnerable neurons, and that made all the difference, says Johnson. These special mice were engineered in collaboration with Albee Messing, a professor in the UW-Madison School of Veterinary Medicine and also an investigator at the Waisman Center. “It’s extremely difficult to increase glutathione in the central nervous system,” Johnson says. “You can’t just shoot it into people or animals. But we found a 25 percent increase in the molecule in the spinal cords.”
Although the mice did eventually die of ALS, they lived longer, and the disease appeared 17 days later than in mice that lacked the extra Nrf2 gene, Johnson says. “This was a very aggressive model of ALS, so a life extension of 21 days is thought to be pretty significant, roughly equivalent to five to 10 years in human patients.“
The inserted Nrf2 gene was only active in support cells called astrocytes, which promote health among the neurons that actually carry nerve signals, Johnson explains. “We have taken this normal function of producing antioxidants and added to it. It’s like putting the astrocytes on steroids.”
Experiments performed on mouse astrocytes and nerve cells in a dish confirmed the source of the protection, Johnson adds. “We can completely reverse the toxicity of the sick astrocytes. The mutated protein that causes ALS is still there, but Nrf2 makes glutathione that completely blocks it.”
Although the mice that Johnson tested carried the inherited form of ALS, most patients do not have an inherited disease. However, Johnson says the mice are still a good testbed for ALS treatments. “The endpoints that we are blocking, including death of neurons and separation of neurons from the muscle, are seen in all forms of ALS; that’s what makes this so exciting. We are not targeting the mutant protein that causes the disease; we are targeting the astrocytes’ mechanism that preserves the neurons. The mutant protein is still in all cells of the spinal cord; we are just over-expressing the Nrf2 gene — causing it to make more glutathione — and that provides the protection.”
Nrf2 activates a system, or pathway, that is also attracting interest from researchers working on Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and stroke, says Johnson. “It’s been exciting. This hypothesis came to me when I was in graduate school in 1990, and this year it seems to be coming to fruition” as a possible treatment for several neurodegenerative diseases.
The results may be promising, but inserting genes, or gene therapy, has had few successes to date. Yet by positively identifying the chemical pathway that keeps neurons healthy in ALS, Johnson is in a position to search for a drug that can enter the brain and activate the Nrf2 system. That quest is already under way at an automated screening facility at UW-Madison, where more than 50,000 molecules are being tested for their ability to activate Nrf2.
Years of research will be needed before today’s results can be translated into a treatment for patients, however. “If everything worked perfectly, we probably could have something in two to three years, but the odds of that happening are pretty low,” says Johnson. “But in five to eight years, I hope to have something can get through all the regulatory hoops.”
Finding that one mechanism is involved in several neurodegenerative diseases is significant, Johnson says, because it attracts a broader group of scientists and funders to the work. “Something seems to be going wrong with the neurons because the astrocyte does not function right. Now, it looks like we have the potential to fix the astrocyte, so it can preserve the neurons for a longer period.”
Delinda Johnson and Daniel Sirkis were also members of the UW-Madison research team. The study was funded by the Robert Packard Center for ALS Research at Johns Hopkins, the ALS Association and National Institutes of Health grants.
David Tenenbaum | Newswise Science News
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
17.01.2017 | Earth Sciences
17.01.2017 | Materials Sciences
17.01.2017 | Architecture and Construction