Location Triggers Fragile X Protein to Reverse Its Function | Spectrum

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Built for Multitasking: FMRP binds a different set of mRNAs near synapses than in the body of a neuron.

FMRP, the protein associated with fragile X syndrome, binds different molecules depending on its location in the neuronsaccording to a new study in mice.

Fragile X syndrome, which often coexists with autism, is the most common form of inherited intellectual disability. People with the disease have a mutation in the RMF1 gene that prevents their cells from producing FMRP.

FMRP regulates the production of about 1,000 other proteins by binding to messenger RNA (mRNA). At the level of the synapses, this regulation makes it possible to strengthen or weaken the connections between neurons, which facilitates learning and the formation of memories.

But FMRP is present in all neurons, and many of the mRNAs it binds to have functions unrelated to synapse formation, says the lead researcher Robert Darnell, professor and chief medical officer at Rockefeller University in New York. So it was not clear why the protein locks onto such mRNA diversity, he says.

The new work shows that FMRP plays a distinct role in the body of neurons, distinct from its action at synapses, and binds to mRNA involved in the regulation of chromatin, the complex of DNA and proteins wound in the core.

The results help explain “how FMRP performs its specific functions despite the fact that it binds so many different mRNAs,” explains Christina Gross, associate professor of neurology at Cincinnati Children’s Hospital Medical Center in Ohio, who was not involved in the study. “It has different functions depending on its location.”

DArnell and his colleagues engineered mice to express fluorescently tagged FMRP in a subtype of excitatory neurons in the hippocampus, a brain region critical for learning and memory. Then, using a specialized technique dubbed CLIP for short, they irradiated the animals’ brains to essentially freeze any protein-bound mRNA in place.

The researchers dissected brain tissue to report where in a cell each fluorescently labeled FMRP was found, then processed the tissue to identify mRNAs bound by the protein.

“What we found was completely unexpected,” says Darnell.

He and his colleagues identified the 1,265 FMRP-bound mRNAs in hippocampal neurons, similar to what had been observed in previous research. But mRNAs fell into two distinct groups based on their location: those found in the dendrites of neurons play a role in synaptic plasticity, while those located in the cell body are involved in chromatin regulation.

In both places, FMRP acts as a brake, preventing ribosomes – tiny cellular structures that translate mRNA into proteins – from doing their job. It is thought that electrical activity releases this brake, leading to the production of proteins which, at the level of the dendrites, can strengthen or weaken the synapses. When electrical activity at the dendrites of a cell becomes strong enough to cause the neuron to fire an action potential, it also releases the FMRP brakes in the cell body, and ribosomes there produce proteins that alter gene expression, the researchers suggest.

One explanation for FMRP’s dual function may be that the change in gene expression serves to reduce the cell’s activity before it spirals out of control, Darnell explains, thereby preventing seizures. Or, conversely, it can help increase a cell’s sensitivity when needed. The results were published in eLife in December.

“This fits well with the idea that memory and protein synthesis-dependent learning might depend on this fragile X protein,” says Darnell. It may also explain the increased incidence of seizures in people with fragile X syndrome and autism, he says.

JThe mice designed for this study, along with the new location-specific list of FMRP-related mRNAs, are important resources for the neuroscience community, says Gary Basselprofessor of cell biology at Emory University in Atlanta, Georgia, who was not involved in the study.

“What the neuroscience community needs to do now is go through these lists,” he says, and identify which mRNAs are linked to long-term memory impairments and other difficulties related to fragile X syndrome. . “They may be drug targets down the road.”

Darnell says he and his colleagues are also thinking about it: “We don’t understand much about autism and intellectual ability, or disability, in the context of problems. If you want to direct drug therapies or enhancements, you would like to know what areas of the brain and what types of neurons are involved. It opens the door to that.

Although the researchers studied FMRP in just one type of neuron, it’s likely the protein has a similar function throughout the brain, Bassell says. “It’s a hypothesis that needs to be tested.”

And because people with fragile X syndrome often have difficulty with executive functions, such as making plans and adapting behaviors, it would be useful in future studies to examine the role of FMRP in the prefrontal cortex. , the part of the brain that is needed for these higher levels. -the thought of order, said Bassell.

Cite this article: https://doi.org/10.53053/YLNN7633


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