Scientists Discover Molecular Process Linking Fragile X and Autism
Researchers have discovered that the fragile X mental retardation protein (FMRP) — the key protein lacking in fragile X syndrome — interacts with small fragments of a gene called eIF4G to control the production of proteins involved in nerve cell communication and memory.
The findings were reported in a study, “Autism-Misregulated eIF4G Microexons Control Synaptic Translation and Higher Order Cognitive Functions,” published in the journal Molecular Cell.
Fragile X, the most frequent genetic cause of autism, is caused by mutations in the FMR1 gene, which provides instructions for making FMRP. People with fragile X lack FMRP, which controls the production of several other proteins at synapses — the sites where nerve cells communicate.
In the study, researchers at the University of Toronto and their colleagues discovered that, in mice, FMRP forms a complex with small bits of the eIF4G gene, known as microexons, to control the production of synaptic proteins — receptors, ion channels, and other signaling molecules — that are required to maintain nerve cell communication.
They also found that these microexons form in the animals’ brain by alternative splicing, the process that enables the production of different proteins from the same gene.
This FMRP-microexon complex acts like a brake, holding off the production of synaptic proteins until a new experience — translated into neural activity — comes along, removing the brake and allowing these proteins to be made.
“It’s important to control brain responses to experience. This brake in protein synthesis [production] is removed upon experience and we think it allows formation of new memories,” Thomas Gonatopoulos-Pournatzis, PhD, the study’s lead author, said in a press release.
However, when researchers used the gene-editing tool CRISPR/Cas9 to specifically delete these eIF4G microexons in the animals, the brake was weakened and no longer able to hold off protein production. This led to massive production of synaptic proteins, and to the disruption of neural signals involved in synaptic plasticity and memory formation. Synaptic plasticity refers to the ability of synapses to strengthen or weaken over time, which is essential to adapt to new information.
Mice lacking these eIF4G gene fragments showed autistic-like features and behaviors, including lack of appropriate social behaviors, as well as poor learning and memory.
These findings, coupled with the fact that excessive production of synaptic proteins had also been reported in the absence of FMRP, suggested that fragile X and other forms of autism might share a common molecular mechanism.
“These results thus reveal a unique mechanism through which alternative splicing and translation [protein production from RNA] are coupled to control higher-order cognitive functioning,” the researchers wrote.
Gonatopoulos-Pournatzis added: “It’s very important to understand the mechanisms that underlie autism, especially in idiopathic forms where it is not clear what the underlying causes are. Not only have we identified a new mechanism that contributes to this disorder, but our work may also offer a more rational development of therapeutic strategies.”
According to the team, a possible therapeutic strategy to improve social behavior and ease cognitive impairments in individuals with autism could involve the use of small molecules that stimulate the splicing of eIF4G microexons.