Fragile X Breakthrough

Prof. Mark Bear identified the molecular malfunction in the brain that underlies fragile X syndrome, a common cause of mental retardation that also appears in some people with autism. Photo: Len Rubenstein

Prof. Mark Bear identified the molecular malfunction in the brain that underlies fragile X syndrome, a common cause of mental retardation that also appears in some people with autism. Photo: Len Rubenstein

Mark Bear’s fascination with neuroscience began with the shocking news that President John F. Kennedy had been shot. Although Bear was only six at the time, he vividly remembers the television coverage. “They were talking about the brain and what it would be like if he survived. I just remember being amazed that I was really the product of this organ in my skull.”

Now the Picower Professor of Neuroscience at MIT, Bear has devoted his career to understanding how that organ works. In a recent breakthrough that could have profound implications for psychiatric medicine, he identified the molecular malfunction that underlies fragile X syndrome, a common cause of mental retardation that also appears in five percent of people with autism. As a result of his findings, several drugs that could correct the disorder are now in clinical trials.

“I’m not an autism researcher. I’m a basic neuroscientist,” says Bear. “I have always believed that basic neuroscience is going to yield the fundamental understanding of brain function that will provide insights into new treatments. What’s taken me by surprise is that it looks like we’re very close to achieving that.”

In his laboratory at the Picower Institute for Learning and Memory, Bear studies synaptic plasticity — how the synapses, or connections, between brain cells change in response to experience. Several years ago, while investigating the causes of weak synapses, Bear found a culprit: excessive protein synthesis. A molecule called mGluR5 (metabotropic glutamate receptor sub-type 5) accelerates protein synthesis as a means to facilitate signal transmission through the brain. But in some cases, it overdoes its job. When Bear and his colleagues asked why, “We ran into a protein in the brain called the fragile X mental retardation protein, FMRP.”

It was already known that individuals with fragile X syndrome lack FMRP because they have mutations in the X chromosome’s FMR1 gene, which encodes the protein. It was not known, however, exactly what FMRP did at the synapse. Bear was the first to show that it counterbalances mGluR5 by repressing protein synthesis. Without it, protein synthesis runs amok, resulting in the myriad symptoms of fragile X syndrome: altered brain development and memory, seizures, anxiety, and abnormal body growth.

“It occurred to us that we could correct fragile X by bringing the system back into normal balance,” says Bear. Through a 50 percent reduction of mGluR5 in mice modeling the disease, they accomplished just that. The technique improved the animals’ brain development and memory, restored normal body growth, and reduced seizures. Bear’s laboratory used genetic engineering to achieve its result, but the class of drugs now in human trials — mGluR5 blockers — appears to do the same thing.

While fragile X syndrome is genetically linked to autism, it and other conditions that stem from a single gene mutation, such as Rett syndrome, comprise only a fraction of the disorders along what is known as the autism spectrum. Many genes are thought to be implicated in autism, and they remain largely unidentified. “We have a long way to go to understand autism. It’s a complicated disease,” Bear concedes.

However, the insights gained from his fragile X study represent a crucial advance in understanding how a particular genetic mutation alters brain function. “We’re trying to figure out what’s different in the brains of individuals along the autism spectrum. We start with genetically defined disorders, even if they’re rare, because we can use animal models of the disease to pinpoint how the brains function differently,” says Bear. “This knowledge may suggest therapeutic approaches for the treatment of many cases of autism, even before we have identified their underlying causes.”

If the drug trials based on Bear’s fragile X research prove successful, this approach could become a new paradigm for psychiatric drug discovery.

by Lauren Clark |

 

On Topic: , , , ,

Prof. Mark Bear identified the molecular malfunction in the brain that underlies fragile X syndrome, a common cause of mental retardation that also appears in some people with autism. Photo: Len Rubenstein

Prof. Mark Bear identified the molecular malfunction in the brain that underlies fragile X syndrome, a common cause of mental retardation that also appears in some people with autism. Photo: Len Rubenstein

Article Tools

  • More about: , , , ,
  • RSS Feed