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Potential New Treatment for Fragile X Targets One Gene To Affect Many

Summary: According to researchers, treatment that target chromatin remodelers may provide new avenues of treatment for Fragile X Syndrome and other autism spectrum disorders.

Source: Rockefeller University.

In Fragile X Syndrome–the leading genetic form of intellectual disability and autism–the effects of a single defective gene ripple through a series of chemical pathways, altering signals between brain cells. It’s a complex condition, but new research from Rockefeller University finds that inhibiting a regulatory protein alters the intricate signaling chemistry that is responsible for many of the disease’s symptoms in animal models. The work, published in Cell, offers insight into how redundant mechanisms control the amount of protein in a cell and provides a path to possible therapeutics for the autism spectrum disorders.

The work centers on a group of proteins–known as chromatin remodeling proteins–that control gene expression. Chromatin remodelers work by adding chemical tags to DNA, regulating the cellular machinery that transcribes genes into messages.

“Drugs that target chromatin remodelers are already in clinical trials to treat cancers like leukemia,” says 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.” The new research suggests that chromatin remodeling proteins may similarly play a key role in Fragile X Syndrome. By targeting chromatin remodelers in animals, the scientists were able to successfully alleviate symptoms of the disease.

Image shows brain slices.

Mouse brains with Fragile X Syndrome (lower) lose the ability to regulate proteins like Brd4 (green). NeuroscienceNews.com image is credited to The Rockefeller University.

Researchers have known for some time that Fragile X Syndrome is caused by defects in a single gene, known as FMRP, but exactly how FMRP affects neural function has remained a mystery.

A break came in 2011, when Rockefeller’s Robert B. Darnell, Robert and Harriet Heilbrunn Professor and a Howard Hughes Medical Institute Investigator, identified hundreds of cellular messages that were associated with FMRP, many of which encode proteins that are involved in neural function. Specifically, these proteins are required at the synapse, the space between two neurons where chemical communications are exchanged. In healthy patients, FMRP binds to the cellular messages and stops them from becoming proteins. But in patients with Fragile X Syndrome, the researchers found that the defective form of FMRP can no longer effectively inhibit protein production, increasing the amount of these synaptic proteins in the cell.

“The results made sense–this is a neurological disorder and we see an effect on proteins involved with neural function,” Darnell explains. As a result, scientists and clinicians alike sought out compounds that could inhibit the synaptic proteins, circumventing the need for FMRP. But in clinical trials, the drugs have been disappointing.

The initial hypothesis couldn’t be the whole story. Korb teamed up with Darnell and David Allis, the Joy and Jack Fishman Professor and head of Rockefeller’s Laboratory of Chromatin Biology and Epigenetics, to revisit the first set of results. They found that chromatin remodelers formed a second class of messages that were significantly associated with FMRP.

Korb and her colleagues then generated cells without FMRP and found that without it, there is an increase in specific chromatin remodeling proteins in the cell. This increase, in turn, causes an increase in the amount of synaptic proteins in the cells.

The researchers borrowed from the cancer biology field and used a drug to inhibit a specific chromatin remodeling protein known as Brd4. “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 says.

Inhibitors for chromatin remodeling proteins may be a potential treatment not only for Fragile X Syndrome but other autism spectrum disorders as well. Previous research from Darnell and his colleagues has demonstrated that chromatin remodeling proteins are also affected in other types of autism. More broadly, the research offers a glimpse into the complex and often redundant networks that even healthy cells use to control gene expression and human behavior.

About this neuroscience research article

Source: Katherine Fenz – Rockefeller University
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to The Rockefeller University.
Original Research: Abstract for “Excess Translation of Epigenetic Regulators Contributes to Fragile X Syndrome and Is Alleviated by Brd4 Inhibition” by Erica Korb, Margaret Herre, Ilana Zucker-Scharff, Jodi Gresack, C. David Allis, Robert B. Darnell in Cell. Published online August 17 2017 doi:10.1016/j.cell.2017.07.033

Cite This NeuroscienceNews.com Article
Rockefeller University “Potential New Treatment for Fragile X Targets One Gene To Affect Many.” NeuroscienceNews. NeuroscienceNews, 3 November 2017.
<http://neurosciencenews.com/fragile-x-gene-7866/>.
Rockefeller University (2017, November 3). Potential New Treatment for Fragile X Targets One Gene To Affect Many. NeuroscienceNews. Retrieved November 3, 2017 from http://neurosciencenews.com/fragile-x-gene-7866/
Rockefeller University “Potential New Treatment for Fragile X Targets One Gene To Affect Many.” http://neurosciencenews.com/fragile-x-gene-7866/ (accessed November 3, 2017).

Abstract

Excess Translation of Epigenetic Regulators Contributes to Fragile X Syndrome and Is Alleviated by Brd4 Inhibition

Highlights
•FMRP regulates chromatin-associated proteins in addition to synaptic proteins
•Misregulation of chromatin contributes to Fragile X syndrome
•Inhibition of Brd4 can alleviate transcriptional dysfunction and phenotypes of FXS

Summary
Fragile X syndrome (FXS) is a leading genetic cause of intellectual disability and autism. FXS results from the loss of function of fragile X mental retardation protein (FMRP), which represses translation of target transcripts. Most of the well-characterized target transcripts of FMRP are synaptic proteins, yet targeting these proteins has not provided effective treatments. We examined a group of FMRP targets that encode transcriptional regulators, particularly chromatin-associated proteins. Loss of FMRP in mice results in widespread changes in chromatin regulation and aberrant gene expression. To determine if targeting epigenetic factors could reverse phenotypes associated with the disorder, we focused on Brd4, a BET protein and chromatin reader targeted by FMRP. Inhibition of Brd4 function alleviated many of the phenotypes associated with FXS. We conclude that loss of FMRP results in significant epigenetic misregulation and that targeting transcription via epigenetic regulators like Brd4 may provide new treatments for FXS.

“Excess Translation of Epigenetic Regulators Contributes to Fragile X Syndrome and Is Alleviated by Brd4 Inhibition” by Erica Korb, Margaret Herre, Ilana Zucker-Scharff, Jodi Gresack, C. David Allis, Robert B. Darnell in Cell. Published online August 17 2017 doi:10.1016/j.cell.2017.07.033

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