Additional Nrf2 targets astrocytes’, which preserve neurons, according to study in Journal of Neuroscience.

A University of Wisconsin-Madison researcher found that in mice with the inherited form of amyotrophic lateral sclerosis (ALS), those with an extra copy of the Nrf2 gene had a longer life and slower nerve deterioration. The extra gene pushed support cells for the neurons into overdrive, causing them to pump out extra quantities of the anti-oxidant glutathione, explains Marcelo Vargas, a postdoctoral fellow in the laboratory of Jeff Johnson, Ph.D., professor in the School of Pharmacy.


Although the mice tested in this study carried the inherited form of ALS, most patients do not have an inherited disease. Dr. Johnson believes that the mice are still a good test bed 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. 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 overexpressing the Nrf2 gene causing it to make more glutathione and that provides the protection.”


The fact that glutathione was produced alongside the vulnerable neurons made all the difference, according to Dr. Johnson. “It’s extremely difficult to increase glutathione in the central nervous system. 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, Dr. Johnson notes. “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 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, Dr. Johnson reports. “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.”


Researchers at UW-Madison are already screening over 50,000 molecules for their ability to activate Nrf2.


The current findings are published in today’s edition of the Journal of Neuroscience.