mglur5

(Image caption: Alterations of the human 16p11.2 chromosomal region lead to a variety of cognitive disorders, including autism. Credit: Pasieka/Science Source)

New findings reveal genetic brain disorders converge at the synapse

Several genetic disorders cause intellectual disability and autism. Historically, these genetic brain diseases were viewed as untreatable. However, in recent years neuroscientists have shown in animal models that it is possible to reverse the debilitating effects of these gene mutations. But the question remained whether different gene mutations disrupt common physiological processes. If this were the case, a treatment developed for one genetic cause of autism and intellectual disability might be useful for many others.

In a paper published today in the online edition of Nature Neuroscience, a research team led by Mark Bear, the Picower Professor of Neuroscience in MIT’s Picower Institute for Learning and Memory, showed that two very different genetic causes of autism and intellectual disability disrupt protein synthesis at synapses, and that a treatment developed for one disease produced a cognitive benefit in the other. The research was performed by postdoc and lead author Di Tian, graduate student Laura Stoppel, and research scientist Arnold Heynen, in collaboration with scientists at Cold Spring Harbor Laboratory and Roche Pharmaceuticals.

Researching the role of fragile X syndrome

One heritable cause of intellectual disability and autism is fragile X syndrome, which arises when a single gene on the X chromosome, called FMR1, is turned off during brain development. Fragile X is rare, affecting one in about 4,000 individuals. In previous studies using mouse models of fragile X, Bear and others discovered that the loss of this gene results in exaggerated protein synthesis at synapses, the specialized sites of communication between neurons.

Of particular interest, they found that this protein synthesis was stimulated by the neurotransmitter glutamate, downstream of a glutamate receptor called mGluR5. This insight led to the idea, called the mGluR theory, that too much protein synthesis downstream of mGluR5 activation gives rise to many of the psychiatric and neurological symptoms of fragile X. Bear’s lab tested this idea in mice, and found that inhibiting mGluR5 restored balanced protein synthesis and reversed many defects in the animal models.

Different genes, same consequences

Another cause of autism and intellectual disability is the loss of a series of genes on human chromosome 16, called a 16p11.2 microdeletion. Some of the 27 affected genes play a role in protein synthesis regulation, leading Bear and colleagues to wonder if 16p11.2 microdeletion syndrome and fragile X syndrome affect synapses in the same way. To address this question, the researchers used a mouse model of 16p11.2 microdeletion, created by Alea Mills at Cold Spring Harbor Laboratory. 

Using electrophysiological, biochemical, and behavioral analyses, the MIT team compared this 16p11.2 mouse with what they already had established in the fragile X mouse. Synaptic protein synthesis was indeed disrupted in the hippocampus, a part of the brain important for memory formation. Moreover, when they tested memory in these mice, they discovered a severe deficit, similar to fragile X.

Restoring brain function after disease onset

These findings encouraged the MIT researchers to attempt to improve memory function in the 16p11.2 mice with the same approach that has worked in fragile X mice. Treatment with an mGluR5 inhibitor, provided by a team of scientists at Roche led by Lothar Lindemann, substantially improved cognition in these mice. Of particular importance, this benefit was achieved with one month of treatment that began well after birth. The implication, according to Bear, is that “some cognitive aspects of this disease, previously believed to be an intractable consequence of altered early brain development, might instead arise from ongoing alterations in synaptic signaling that can be corrected by drugs.”

Current research indicates that well over 100 distinct gene mutations can manifest as intellectual disability and autism. The current findings are heartening, as they indicate not only that drug therapies might be effective to improve cognition and behavior in affected individuals, but also that a treatment developed for one genetic cause might apply more broadly to many others.

20 October 2013

Serial Killer Blocked

The possibility of developing drugs to treat Alzheimer’s disease, the commonest form of dementia, comes closer as we unravel its complex chemistry. We know that a family of substances called amyloid-beta peptides (ABPs) is a serial killer of brain nerve cells, or neurons – whose spindly extremities vulnerable to attack are stained green in this picture of highly magnified brain tissue. While ABPs are difficult to zap with drugs, a much easier target appears to be a protein in the cell membrane, called mGluR5 which has been shown to play a critical role in the ABPs’ attack plan. In an experiment on mice with a similar condition to Alzheimer’s, their memory and learning ability were restored when mGluR5 was chemically blocked. Whether a safe and effective drug can be developed for use on humans remains to be seen but research is now underway.

Written by Mick Warwicker

Yale University, USA
Juha Lauren and Stephen Strittmatter
Research published in Neuron 79(5): 887–902

Alzheimer’s missing link found: Is a promising target for new drugs

Yale School of Medicine researchers have discovered a protein that is the missing link in the complicated chain of events that lead to Alzheimer’s disease, they report in the Sept. 4 issue of the journal Neuron. Researchers also found that blocking the protein with an existing drug can restore memory in mice with brain damage that mimics the disease.

“What is very exciting is that of all the links in this molecular chain, this is the protein that may be most easily targeted by drugs,” said Stephen Strittmatter, the Vincent Coates Professor of Neurology and senior author of the study. “This gives us strong hope that we can find a drug that will work to lessen the burden of Alzheimer’s.”

Scientists have already provided a partial molecular map of how Alzheimer’s disease destroys brain cells. In earlier work, Strittmatter’s lab showed that the amyloid-beta peptides, which are a hallmark of Alzheimer’s, couple with prion proteins on the surface of neurons. By an unknown process, the coupling activates a molecular messenger within the cell called Fyn.

In the Neuron paper, the Yale team reveals the missing link in the chain, a protein within the cell membrane called metabotropic glutamate receptor 5 or mGluR5. When the protein is blocked by a drug similar to one being developed for Fragile X syndrome, the deficits in memory, learning, and synapse density were restored in a mouse model of Alzheimer’s.

Strittmatter stressed that new drugs may have to be designed to precisely target the amyloid-prion disruption of mGluR5 in human cases of Alzheimer’s and said his lab is exploring new ways to achieve this.