Researchers link enzyme inactivation to delaying paralysis

Researchers at the School of Medicine recently published a study in Nature Cell Biology detailing their discovery that the inactivation of the sirtuin-1 enzyme (SIRT1) in mice may delay the onset of paralysis caused by demyelinating injuries like multiple sclerosis.

Demyelination — damage to neurons’ myelin sheath — can be caused by a variety of factors, including genetics and autoimmune diseases. Researchers found that when SIRT1 is inactivated, the production of myelin-forming cells in the adult mouse brain increased.

“The results that we have are still preliminary, but they indicate that mice that are deficient for this SIRT1 enzyme are better in terms of resisting demyelinating injuries,” said Associate Professor of Genetics Anne Brunet, the principal investigator at the lab that conducted the research.

According to Brunet, SIRT1 proteins are known to play a role in many of the body’s functions, particularly in its metabolic processes. Research on the impact of SIRT1 in adult stem cells led Brunet’s lab to the unexpected discovery that a deficiency in that protein increases the production of oligodendrocytes, or myelin-forming cells.

“We’ve always been interested in the role of genes that regulate lifespan or health in the brain,” Brunet said about the work. “In particular in the brain we’ve been interested in the population of cells that have regenerative potential, which are the neural stem cells in the brain.”

The experiments were conducted by Victoria Rafalski Ph.D. ’11 P.D. ’13, a postdoctoral scholar at the University of California, San Francisco, who was a graduate student working in Brunet’s lab at the time of the research.

Brunet said that her researchers also had “great collaborations” with Professor of Neurobiology Ben Barres, an expert in oligodendrocytes, and Professor of Pediatrics Lawrence Steinman, an expert in multiple sclerosis and demyelinating diseases.

Although inactivating the SIRT1 enzyme delayed paralysis in mice with demyelinating diseases, the treatment does not directly translate to humans with the same diseases. The study’s abstract notes, however, that the identification of these enzymes could assist in the creation of therapies for demyelinating injuries and diseases.

Though Brunet emphasized that it is still “very early in the process” and expressed aversion to giving false hope about potential multiple sclerosis treatments, she acknowledged that the study’s discovery opens up new areas for future research.

“That could be potentially an interesting avenue for diseases in which the myelin sheath generated by oligodendrocytes is injured,” Brunet said. “Another potential avenue would be for injuries that involve myelin.”

Brunet cited spinal cord injuries as another area where further research on SIRT1 could be beneficial.

“Another potential avenue would be for demyelinating injuries — for example, spinal cord injuries, where it’s possible that having more oligodendrocytes or finding new ways to regenerate or expand the pool of oligodendrocytes could be also helpful in this context,” Brunet said.

The lab’s future research will focus on the influence of age on the production of oligodendrocytes and on specific diseases that affect myelin.

“We’re very interested in understanding how it could connect with aging, because that’s what the lab is doing,” Brunet said.