Fragile X syndrome (FXS) robs the brain of a protein that plays a major role in the way neurons communicate and that is essential for brain development, learning and memory.
A team of scientists has discovered new information about how FXS interferes with signaling between the nucleus of neurons and the synapse, the outer reaches of the neuron where two neurons communicate via chemical and electrical signals. The discovery should help lead the way to the development of new treatments for FXS, the most common form of inherited mental retardation and also a genetic contributor to some types of autism and epilepsy.
Translation of an organism's genetic information begins in the nucleus of a cell, where the DNA sequence (gene) is copied into an mRNA molecule, then exported into the cell's cytoplasm and translated into protein molecules.
FXS is caused by the silencing of a single gene, which normally would encode for the expression of the fragile x mental retardation protein (FMRP)--an mRNA (messenger RNA) binding protein. mRNA binding proteins are known to be key regulators of gene expression because they act as master regulators of other mRNAs and broadly influence how proteins are synthesized from mRNAs.
The precise functions for FMRP have been unclear, but scientists recently have learned that FMRP is able to bind and regulate several mRNAs that are present at synapses in the brain. Each mRNA molecule can be translated many times at the synapse, producing many copies of the encoded protein and providing an efficient way for a neuron to supply its synapse with essential proteins needed for communication. Since mRNAs can be turned on or off, each synapse can decide for itself whether or not new proteins are needed to promote signaling. Proper signaling at synapses is essential for the complex wiring of connections that must occur during brain development and during learning and memory. In FXS, there are defects in both the structure and signaling at synapses, due to the lack of FMRP regulation of mRNAs at synapses. Until now, a major unanswered question has been how FMRP and its bound mRNAs are delivered to axons and dendrites Ð the tentacle-like projections of neurons-- and to the synapses at their outer extremities.
"A major challenge for the field of neuroscience has been to understand how a selective group of mRNAs can be transported long distances from the nucleus, where the RNA is made, to reach the synapses, where this select group of mRNAs can be translated into the protein molecules that are needed to enable signaling," says Gary J. Bassell, professor of cell biology and neurology at Emory University School of Medicine. "This mechanism of mRNA transport into axons and dendrites and its translation at synapses is critical for synapse signaling during learning, memory and cognition."
Bassell and his Emory colleagues have developed high resolution microscopic imaging tools to visualize FMRP in live neurons, allowing them to track the movements of FMRP and associated mRNA molecules along dendrites, using cultured neurons isolated from the hippocampus of mouse embryos.
The researchers discovered that FMRP binds to a molecular motor, which allows it to carry its bound mRNAs in the form of particles out into the dendrites.
"FMRP seems to be quite a clever protein that acts like a postal carrier to deliver messages to the synapse, enabling and sustaining their continued signaling," says Bassell.
In a mouse model of FXS, the investigators discovered that mRNAs are not motored into dendrites in response to synaptic signaling and thus cannot allow for local protein synthesis at synapses needed to sustain the synaptic signaling between nerve cells. In essence, the ability of the nerve cell to communicate from the nucleus to the synapse is lost in fragile X.
The researchers also were able to identify the select group of mRNAs that the neuron ships into dendrites via FMRP. Knowing which molecules within the FMRP pathway function at synapses should facilitate the development of new treatment strategies and drug interventions for FXS.
The research team was led Bassell and Robert H. Singer, PhD, professor of anatomy & structural biology at the Albert Einstein College of Medicine. First author was Jason B. Dictenberg of Hunter College, City University of New York and Albert Einstein College of Medicine. Other authors included Sharon A. Swanger, Emory University Department of Cell Biology and Laura N. Antar, Albert Einstein College of Medicine. The research was funded by the National Institutes of Health and the Fragile X Research Foundation.
Reference: A Direct Role for FMRP in Activity-Dependent Dendritic mRNA Transport Links Filopodial-Spine Morphogenesis to Fragile X Syndrome. Published online at Developmental Cell. June 10, 2008.