NOV 06, 2017 07:29 AM PST

Potential Treatment for Fragile X Syndrome ID'ed

WRITTEN BY: Carmen Leitch

Mutations in one gene cause fragile X syndrome, which is the most common genetic form of autism and intellectual disability; it is further described in the video. New work by researchers at Rockefeller University has opened up a potential therapeutic avenue for the disorder; they have revealed that blocking a type of regulatory protein impacts the complex mechanisms that cause the disease. 

Reporting in Cell, the investigators have found that targeting chromatin remodelers relieved symptoms of the disease in an animal model. Chromatin remodelers act to modify DNA with chemical tags, which means they affect how many different genes are expressed. It is very likely that chromatin remodeling proteins have a role in fragile X syndrome.

"Drugs that target chromatin remodelers are already in clinical trials to treat cancers like leukemia," said study author Erica Korb, a postdoctoral researcher at Rockefeller. "It is an attractive approach because a single inhibitor allows you to target a whole network of genes at once." 

It has been known for awhile that defects in the FMRP gene cause Fragile X Syndrome, but it was not known how. A breakthrough happened in 2011; Rockefeller's Robert B. Darnell, Robert and Harriet Heilbrunn Professor and a Howard Hughes Medical Institute Investigator, found hundreds of cellular signals that were linked to FMRP. These signals were mRNAs that act as intermediaries between genes and proteins to be synthesized; they encoded for proteins that function at the synapse of neurons, where two nerve cells meet and exchange chemical information.

It was found that typically, the FMRP protein acts to inhibit the mRNAs, binding to them, so they do not become proteins. But in fragile X syndrome patients, the FMRP is defective and cannot stop the production of new proteins from the mRNAs, which raises the cellular levels of synaptic proteins.

"The results made sense; this is a neurological disorder and we see an effect on proteins involved with neural function," Darnell explained. 

That sent doctors and scientists scrambling to find compounds that could interfere with the synaptic proteins to compensate for the defective FMRP. Clinical trials were a disappointment, however. There was likely more to the story.

Korb collaborated with Darnell and David Allis, the Head of Rockefeller's Laboratory of Chromatin Biology and Epigenetics, to reassess the first data set. Chromatin remodelers were found to form another class of cellular signals that were significantly linked to FMRP. Korb and her team created cells lacking FMRP; they saw an increase in the cellular levels of certain chromatin remodeling proteins. The levels of synaptic proteins in the cells were subsequently raised.

Mouse brains with Fragile X Syndrome (lower) lose the ability to regulate proteins like Brd4 (green). / Credit/copyright: The Rockefeller University

Cancer biologists have established a way to inhibit the chromatin remodeling protein, Brd4, so the scientists tried it. "The results were exciting. In cellular and animal models of Fragile X Syndrome, we saw a return to normal numbers of neuronal synapses and a decrease in behavioral symptoms," Korb revealed.

Chromatin remodeling proteins have been implicated in some types of autism, and inhibitors of these proteins may be a new kind of therapeutic for autism spectrum disorders as well as fragile X syndrome. The research also shows how redundancy in the cell gives rise to complex networks that function to regulate gene expression and by extension, human health and behavior.

Sources: AAAS/Eurekalert! Via Rockefeller University, Cell

About the Author
  • Experienced research scientist and technical expert with authorships on 28 peer-reviewed publications, traveler to over 60 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
You May Also Like
NOV 17, 2018
Videos
NOV 17, 2018
Using Genetic Research to Improve Animal Conservation and Care
A group of Peters's Angolan colobus monkeys were brought to US zoos from East Africa in the 80s, but little is known about them....
NOV 20, 2018
Videos
NOV 20, 2018
A Major Grant Aims to Improve our Understanding of Age-related Cognitive Decline
The American Heart Association has teamed up with the Allen Initiative in Brain Health and Cognitive Impairment to award the Salk Institute $19.2 million....
NOV 28, 2018
Microbiology
NOV 28, 2018
A Deadly Microbe Lurks on the Skin of Many People
There are some well-known bacterial pathogens that can present a major threat to health, but a lesser-known microbe may be just as big of a danger....
DEC 11, 2018
Genetics & Genomics
DEC 11, 2018
Dust with High Levels of Triclosan has More Antibiotic Resistance Genes
Researchers have found that some dust contains high amounts of a common antimicrobial agent called triclosan....
DEC 26, 2018
Genetics & Genomics
DEC 26, 2018
How Cell-free DNA Can Teach us About Aging
Scientists have long been seeking to understand aging. Researchers found age-related changes in cell-free DNA....
DEC 29, 2018
Genetics & Genomics
DEC 29, 2018
Kidney Disease Risk Variant Found in New Populations
While we all carry the same genes in our genome, small variations within those genes can cause huge biological changes....
Loading Comments...