Recovery from Stroke and Spinal Injury Aided by Gene Deletion

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Source: NIH
Genetic manipulation and DNA modification concept.


In response to injury, cells typically go to work trying to repair the damage. While this healing process is amazingly effective for many tissue types, for various neuronal injuries the repair process is either extremely slow or nonexistent. However now, a new study from investigators at the University of Texas Southwestern’s O'Donnell Brain Institute has found a genetic trigger that may improve the brain's ability to heal from a range of debilitating conditions, from strokes to concussions and spinal cord injuries.    

Finding from the new study, published recently in Cell Reports (“Leucine Zipper-Bearing Kinase Is a Critical Regulator of Astrocyte Reactivity in the Adult Mammalian CNS”), shows that turning on a gene inside astrocytes results in a smaller scar and, potentially, more effective recovery from injury. These results have implications for treating several brain conditions through gene therapy targeting astrocytes.

Genetically modified astrocytes (red) line the lesion border in the injured spinal cord. A new mouse study shows that triggering a gene inside astrocytes activates the star-shaped cells and may improve the brain's ability to heal from a range of debilitating conditions, from stroke to concussions and spine injuries. [UT Southwestern]
Genetically modified astrocytes (red) line the lesion border in the injured spinal cord. A new mouse study shows that triggering a gene inside astrocytes activates the star-shaped cells and may improve the brain’s ability to heal from a range of debilitating conditions, from stroke to concussions and spine injuries. [UT Southwestern]

“We've known that astrocytes can help the brain and spinal cord recover from injury, but we didn't fully understand the trigger that activates these cells,” explained co-senior study investigator Mark Goldberg, M.D., chairman of neurology and neurotherapeutics at UT Southwestern. “Now we'll be able to look at whether turning on the switch we identified can help in the healing process.”

In the current study, the researchers deleted the leucine zipper-bearing kinase (LZK) gene in astrocytes of one group of injured mice, which decreased the cells' injury response and resulted in a larger wound on the spinal cord. Conversely, the scientists overexpressed the gene in other injured mice, which stimulated the cells' injury response and resulted in a smaller scar. Overexpressing the gene in uninjured mice also activated the astrocytes, confirming LZK as a trigger for astrogliosis.

“Using genetic loss and gain-of-function analyses in vivo, we showed that the conserved MAP3K13 (also known LZK) promotes astrocyte reactivity and glial scar formation after CNS injury,” the authors wrote. “Inducible LZK gene deletion in astrocytes of adult mice reduced astrogliosis and impaired glial scar formation, resulting in increased lesion size after spinal cord injury. Conversely, LZK overexpression in astrocytes enhanced astrogliosis and reduced lesion size. Remarkably, in the absence of injury, LZK overexpression alone induced widespread astrogliosis in the CNS and upregulated astrogliosis activators pSTAT3 and SOX9.”

Reactive astrocytes surround the lesion site in the injured spinal cord.  [UT Southwestern]
Reactive astrocytes surround the lesion site in the injured spinal cord. [UT Southwestern]

Dr. Goldberg added that a smaller scar likely aids the healing process by isolating the injured neurons, similar to how isolating a spreading infection can improve recovery. “But we don't know under what circumstances this hypothesis is true because until now we didn't have an easy way to turn the astrocyte reactivity on and off,” he said.

The investigators stressed that further study is needed to analyze whether a compact scar tissue indeed improves recovery and how this process affects the neurons' ability to reform connections with each other.

Dr. Goldberg's lab will conduct more research to examine the effects of astrogliosis in stroke and spinal cord injuries. The researchers will determine whether turning up LZK in mice in advance of an injury affects its severity. They will then measure how the formation of the compact scar helps or hinders recovery.

“It has been a big mystery whether increasing astrocyte reactivity would be beneficial,” concluded lead study investigator Meifan Amy Chen, Ph.D., instructor of neurology at the Peter O'Donnell Jr. Brain Institute. “The discovery of LZK as an on switch now offers a molecular tool to answer this question.”






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