Specific Piece of FMRP Protein Eases Hyperactivity in Mouse Model

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by Steve Bryson PhD |

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Providing a fragment of the FMRP protein, which is missing in people with fragile X syndrome, eased hyperactivity and restored nerve cell communication in the brain, a study in a mouse model found.

The study, “FMRP(1–297)-tat restores ion channel and synaptic function in a model of Fragile X syndrome,” was published in the journal Nature Communications

The FMRP protein plays a critical role in the specialized connections between nerve cells called synapses. Lack of this protein, caused by mutations in the FMR1 gene, induces a range of developmental problems that include cognitive impairment, learning disabilities, and hyperactivity. 

FMRP is widely produced in the cerebellum, a structure located at the back of the brain. The protein regulates the activity of proteins known as ion channels at the cell membrane, allowing the passage of ions and driving nerve impulses. 

Researchers at the University of Calgary, in Canada, hypothesized that a shortage of FMRP disrupts the synaptic connection between nerve cell projections known as mossy fibers, one of the major inputs to the cerebellum, and cerebellar cells called granule cells.

“If I had to make an analogy, it might be akin to insulin and diabetes,” Raymond Turner, PhD, professor at the University of Calgary’s Cumming School of Medicine and the study’s senior authorsaid in a university press release. “With [fragile X], individuals are missing this protein — let’s try putting it back in.”

Instead of using the full-length FMRP protein, the team used a fragment of FMRP — called FMRP(1–297) — that still maintained function. 

“It’s not a full FMRP molecule at all but rather a fragment with important structural features and functional components that are active in doing things like controlling ion channels or the levels of other proteins,” said Ning Cheng, PhD, a scientist in the Turner lab and a study co-author.

Using brain tissue from mice engineered to lack the FMRP protein (Fmr1 KO mice), the team found that FMRP(1–297) restored the activation of granule cells in a concentration-dependent manner and normalized the response of mossy fibers, which is essential for motor learning.

Results also showed that the effect of FMRP(1–297) on mossy fibers was via its role in an ion channel complex that contains a calcium channel (Cav3) and a potassium channel (Kv2). This finding indicates that the FMRP protein is a member of the Cav3–Kv4 complex.

To test FMRP(1–297) potential in vivo, a small protein called tat was bound to the FMRP(1–297) protein to allow it to cross the blood-brain barrier — a highly selective membrane that shields the brain from large molecules and other cells found in the blood. 

FMRP(1–297)-tat, injected into the animals’ tail, was seen to rapidly spread in the brain.

“In 30 minutes, the protein distributed throughout the brain and accomplished what it’s supposed to do at the single-cell level,” Turner said.

As hyperactivity and anxiety are hallmark symptoms of fragile X, Fmr1 KO mice treated with FMRP(1–297)-tat were put through an open field test to measure motor activity levels, anxiety, and willingness to explore. Hyperactivity lessened with FMRP(1–297)-tat for almost 24 hours.  

FMRP(1–297)-tat also normalized the levels of three essential proteins in brain function, which are altered in the Fmr1 KO mouse model of fragile X.

“We did one injection and we tested for it one day later, and three key proteins that are known to be in Fragile X were still at restored normal levels,” said Xiaoqin Zhan, PhD, the study’s first author.

“These data reveal that FMRP(1-297)-tat can improve function from the levels of protein translation [production] to synaptic efficacy and behaviour in a model of Fragile X syndrome, identifying a potential therapeutic strategy for this genetic disorder,” the scientists wrote. 

The team now plans to investigate other parts of FMRP, testing the protein’s ability to ease cognitive disorders associated with fragile X. 

“Unlike a lot of drug therapies where you hope you can get your drug to one specific group of cells, FMRP is expressed in just about every cell in the brain, so an all-encompassing wide-based application is what you want,” Turner said. 

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