October 2014
Researchers have identified a key enzyme in astrocytes that turns on during the progressive stage of multiple sclerosis, apparently boosting the local immune response and promoting neurodegeneration. The team is following up by testing a repurposed drug that targets the enzyme in mice and human cells.
October 2014
Researchers have identified a key enzyme in astrocytes that turns on during the progressive stage of multiple sclerosis, apparently boosting the local immune response and promoting neurodegeneration. The team is following up by testing a repurposed drug that targets the enzyme in mice and human cells.
CAROL CRUZAN MORTON
In the brain and spinal cord, neurons are the undisputed heads of state, the red-carpet celebrities, the pop-icon pinups. They shape who we are, how we think, what we do, and how we know where we are. But astrocytes are gaining a small measure of fame for the power they wield behind the scenes. In health and disease, they control the function and fate of neurons and other cells in nuanced ways that scientists are only beginning to understand.
Recent findings add a new twist to the astrocyte story in multiple sclerosis (MS). Astrocytes, a new study reports, may be a potential target for secondary progressive MS (SPMS), which causes the greatest disability and for which there is no effective treatment. Most people with relapsing-remitting MS (RRMS), the most common form of the disease, eventually move on to the steadily worsening SPMS. Most available therapies treat RRMS by reducing the rate or severity of immune attacks.
In the progressive stage, researchers have found, some astrocytes seem to switch on genes that drive chronic inflammation and neurodegeneration. One particular fatty molecule, lactosylceramide (LacCer), as well as the enzyme (B4GALT6) that makes it, fuel the destructive pattern by turning on a signal to recruit inflammatory monocytes from the blood, experiments in mice and with human brain tissue suggest.
A new study shows that astrocytes promote CNS inflammation through the upregulation of B4GALT6, which in turn makes LacCer in the spinal cord of mice with chronic-progressive EAE. LacCer cycles through a feedback loop that activates microglia and monocytes. Reprinted by permission from Macmillan Publishers Ltd.: Nature Medicine 20:1092-3, copyright 2014.
Importantly, inhibiting the enzyme in mice can suppress the neurotoxic astrocyte activation, Francisco Quintana, Ph.D., and his colleagues at Brigham and Women’s Hospital and Harvard Medical School in Boston report. Their paper was published online September 14 in Nature Medicine (Mayo et al., 2014).
“This is a very important and innovative step forward in understanding how astrocytes get activated and control the influx of inflammatory cells in neurological diseases such as multiple sclerosis,” Ben Barres, M.D., Ph.D., of Stanford University wrote in an email to MSDF. Barres was not involved in the Nature Medicine study. “The mechanisms that control glial activation in brain disease are poorly understood, and this paper highlights a critical role for the glycolipid lactosylceramide in this process. It has the potential to lead to new therapies by controlling unwanted inflammatory cell infiltration.”
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