By Charlene N. Rivera-Bonet, Waisman Science Writer
The hallmarks of Alexander disease, aggregation of misfolded GFAP proteins and dysregulation of brain cells called astrocytes, may be stopped and reversed in rodent models with the inactivation of the transcription factor STAT3.
A recent study published in Cells found that STAT3, a transcription factor that controls the expression of the GFAP gene, drives the increase and accumulation of the GFAP protein in astrocytes seen in Alexander disease. Blocking STAT3 reverses not only the accumulation of the protein, but also the collateral stress and neuroinflammation response in the cells, the study shows.
Alexander disease is a progressive and generally fatal disorder of the central nervous system that results from a mutation in the gene for glial fibrillary acidic protein (GFAP). The mutated gene causes the GFAP protein to misfold and accumulate in astrocytes. This accumulation contributes to toxicity because it triggers a stress response in astrocytes that leads to even more accumulation of the misfolded GFAP protein. “I think there’s a feed forward loop here where once you start the cellular stress response, it takes off,” says Tracy Hagemann, PhD, associate research professor and first author of the study.
Hagemann and Albee Messing, VMD, PhD, professor emeritus of comparative biosciences and senior author of the study, sought to better understand what was driving the increased expression of GFAP by using a combination of genetic approaches to eliminate or reduce activation of STAT3 in mice. “If we get rid of STAT3, do you get rid of the response that’s responsible for upregulating GFAP? Which in the context of Alexander disease, is very problematic because you’re increasing the expression of the mutant protein,” Hagemann says.
In a mouse model of Alexander disease that carries the mutant GFAP gene they first measured levels of active STAT3 in different regions of the brain and spinal cord, finding that STAT3 was mostly expressed in the forebrain as compared to the hindbrain and spinal cord. This pattern of expression coincides with where GFAP accumulates in the mice and in individuals with early onset disease. They also found active STAT3 localized in astrocytes using a brain tissue sample from a person with Alexander disease, showing that STAT3 seems to be active in cells and regions of the brain affected by the disease.
In order to determine if lower levels of STAT3 would have any effects on GFAP, they developed a mouse line that had reduced STAT3. However, even with lower levels of the transcription factor, GFAP was elevated. Lower STAT3 wasn’t enough to stop the disease, so the next step was fully eliminating it.
The tricky part is that fully eliminating STAT3 is fatal because of its involvement in many important cellular processes. So, the scientists developed a mouse model in which they could select when and where STAT3 would be fully “turned off.” The inactivation of STAT3 led to levels of GFAP at or below those measured in mice without Alexander disease at 8 and 12 weeks of age.
In adult mice with already established GFAP and astrocyte pathology, inactivating STAT3 resulted in reduced GFAP expression, and less cellular stress and neuroinflammatory response of astrocytes. It also reversed GFAP accumulation. “This is a critical point, because most patients are not diagnosed until well after the changes in GFAP and tissues are well established,” Messing says. They have yet to see if this reversibility is also possible in humans.
Currently, clinical trials are in progress for a treatment for Alexander disease that directly targets GFAP. Although there is still much research to be done with STAT3, it presents an alternative potential target for treatment, particularly since drugs targeting it are already approved by the Food and Drug Administration (FDA) or in clinical trials. “If we could repurpose drugs that are already approved, that would be great, because that might be able to help more people, more quickly,” Hagemann says.
Hagemann, Messing, and their team will continue to work on the plausibility of a pharmaceutical approach to target STAT3, and other ways of reducing the expression of the mutant GFAP to treat Alexander disease.
This study was funded by grants from the National Institutes of Health National Institute of Neurological Disorders and Stroke (NS093482 and NS110719) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD076892, HD090256 and HD105353), EndAxD and the Juanma Fund.
Caption from image at top of page: Labeling of STAT3 (red) and GFAP (green) in a wild-type mouse hippocampus (first image), followed by mice with the mutated GFAP hippocampus, olfactory bulb, frontal cortex and adjacent to the corpus callosum, in order.
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