A Key Biological Mechanism in Multiple Sclerosis Has Been Identified by Scientists
A key underlying process implicated in multiple sclerosis (MS) – a disease that causes progressive and irreversible damage to nerve cells in the brain and spinal cord, has been defined for the first time by scientists at the Gladstone Institutes. The discovery offers new hope for the people who suffer from MS, a debilitating disease for which there is no cure.
Using animal models the researchers in the laboratory of Gladstone Investigator Katerina Akassogiou, PhD, have identified precisely how a protein that seeps from the blood into the brain sets of a response that, over time, causes the nerve cell damage that is a key indicator of MS. Reporting these findings in the latest issue of Nature Communications, the groundwork was laid for much-needed therapies to treat MS.
MS develops when the body's immune system attacks the brain, afflicting more than two million people worldwide.The attacks from MS lead to a host of symptoms including numbness, fatigue, difficulty walking, paralysis and loss of vision. Some of these symptoms may be delayed with drug therapies, but they do not treat the disease's underlying cause-which is just beginning to be understood by researchers.
"To successfully treat MS, we must first identify
what triggers the disease and what enables its progression,"
said Dr. Akassoglou, who also directs the Gladstone Center for
In Vivo Imaging Research and is a professor of neurology at the
University of California, San Francisco, with which Gladstone is
affiliated. "Here, we have shown that the leakage of
blood in the brain acts as an early trigger that sets off the
brain's inflammatory response—creating a neurotoxic
environment that damages nerve cells."
Dr. Akassogiou and her team were able to reach this conclusion by monitoring the disease's progression in the brain and spinal cord of mice modified to mimic the signs of MS by using advanced imaging techniques. Traditional techniques only show “snapshots” of the disease's pathology. However, this analysis allows researchers to study individual cells within the living brain—and to monitor in real-time what happens to these cells as the disease worsens over time.
"In vivo imaging analysis let us observe in
real-time which molecules crossed the blood-brain barrier,"
said Dimitrios Davalos, PhD, Gladstone staff research scientist,
associate director of the imaging center and the paper's lead
author. "Importantly, this analysis helped us identify
the protein fibrinogen as the key culprit in MS, by
demonstrating how its entry into the brain through leaky blood
vessels impacted the health of individual nerve cells."
A blood protein that is involved in coagulation, fibrinogen, is not found in the healthy brain. However, it is revealed in vivo imaging over different stages of disease that a disruption in the blood-brain barrier allows blood proteins—and specifically fibrinogen—to seep into the brain. A rapid response to fibrinogen's arrival is initiated by microglia—immune cells that act as the brain's first line of defense. They release large amounts of chemically reactive molecules called 'reactive oxygen species.' A toxic environment is created within the brain by this, which damages nerve cells eventually leading to the debilitating symptoms of MS.
By genetically modifying fibrinogen in the animal models, an important strategy to halt this process was found. Without affecting fibrinogen's essential role as a blood coagulant, this strategy was able to disrupt the protein's interaction with microglia. Microglia did not react to fibrinogen's arrival in these models, and did not crate a toxic environment. The mice failed to show the type of progressive nerve cell damage seen in MS as a result.
"Dr. Akassoglou's work reveals a novel target for treating MS—which might protect nerve cells and allow early intervention in the disease process," said Ursula Utz, PhD, MBA, a program director at The National Institutes of Health's National Institute of Neurological Disorders and Stroke, which provided funding for this research."Indeed, targeting the fibrinogen-microglia interactions to halt nerve-cell damage could be a new therapeutic strategy," said Dr. Akassoglou. "At present we are working to develop new approaches that specifically target the damaging effects of fibrinogen in the brain. We also continue to use in vivo imaging techniques to further enhance our understanding of what triggers the initiation and progression of MS. "
Source: Science Codex (30/11/12)
Original Story: Scientists identify key biological mechanism in multiple sclerosis
msrc.co.uk/Multiple Sclerosis Resource Centre
Author: William D.