Fragile X Proteins Linked To Healthy Neuron Development

Two proteins associated with fragile X play a key role in the proper development of neurons in mice, a new study shows. The study also showed that although the two proteins act through distinct mechanisms in the formation of new neurons, they also share some duties.

According to co-author and Waisman Center and Department of Neuroscience Professor Xinyu Zhao:

“This is the first demonstration of the additive function of fragile X proteins in neuronal development.”

Fragile X syndrome is the most common inherited intellectual disability. It is also the greatest single genetic contributor to autism.

Understanding the mechanisms behind fragile X could lead to important revelations about the brain.

Relatively little is known about the underlying mechanisms that lead to the cognitive and learning deficits in fragile X syndrome, Zhao says, making it difficult to devise effective therapies.

FMRP and FXR2P

Zhao studies the two fragile X proteins, FMRP and FXR2P, since doing so could yield new information that ultimately leads to treatment for fragile X and other disorders marked by defects in neuronal development, like autism and schizophrenia.

In the study, published June 4 in the journal Cell Reports, researchers from the University of Wisconsin-Madison Waisman Center and Department of Neuroscience highlighted a new interaction between the FXR2P protein and a specific neuronal receptor, a protein charged with receiving messages and passing along information, and showed that the two work together for proper neuronal development.

Additionally, it revealed that FXR2P and FMRP work together in regulating this receptor’s activity and the maturation of neurons.

A previous study by Zhao’s team showed that both FMRP and FXR2P are integral for new neuron production in adult mice and are important for learning and cognition. In the current study, the research team looked at the function of the proteins in the maturation of newly formed adult neurons.

The Fragile X Mutation

Fragile X is a genetic condition that affects one in 4,000 males and one in 8,000 females. It’s linked to a mutation in the gene that makes the FMRP protein, located on the X chromosome. Up to a third of people with fragile X also have autism.

Children with the syndrome are more prone to attention deficit disorder and a diagnosis on the autism spectrum; display physical features such as flat feet, a prominent jaw and forehead, and a long and narrow face; and may have anxiety.

Additionally, an estimated one in 250 women and one in 500 men carry a “premutation” on the gene that makes FMRP protein, which renders the gene unstable.

Carriers can pass it on to future generations and are at greater risk for a Parkinson’s disease-like disorder called fragile X-associated tremor/ataxia syndrome. They may also be more prone to stress and other challenges.

“The findings suggest that fostering new nerve cell development during the postnatal period may have therapeutic potential for people with fragile X syndrome and other neurological disorders,” says Zhao. “If we can find a way to reactivate the FMRP gene, we may be able to treat the disease.”

Reference:

Weixiang Guo, Eric D. Polich, Juan Su, Yu Gao, Devin M. Christopher, Andrea M. Allan, Min Wang, Feifei Wang, Guangfu Wang, Xinyu Zhao
Fragile X Proteins FMRP and FXR2P Control Synaptic GluA1 Expression and Neuronal Maturation via Distinct Mechanisms
Cell Reports DOI: http://dx.doi.org/10.1016/j.celrep.2015.05.013

Summary

“Fragile X mental retardation protein (FMRP) and its autosomal paralog FXR2P are selective neuronal RNA-binding proteins, and mice that lack either protein exhibit cognitive deficits. Although double-mutant mice display more severe learning deficits than single mutants, the molecular mechanism behind this remains unknown. In the present study, we discovered that FXR2P (also known as FXR2) is important for neuronal dendritic development.

FMRP and FXR2P additively promote the maturation of new neurons by regulating a common target, the AMPA receptor GluA1, but they do so via distinct mechanisms: FXR2P binds and stabilizes GluA1 mRNA and enhances subsequent protein expression, whereas FMRP promotes GluA1 membrane delivery. Our findings unveil important roles for FXR2P and GluA1 in neuronal development, uncover a regulatory mechanism of GluA1, and reveal a functional convergence between fragile X proteins in neuronal development.”

Top: Fragile X chromosome, atomic force microscope, Credit Dr Ben Oostra, Wellcome Images