The production of several large proteins from stored messenger RNAs (mRNAs) — molecules that contain instructions to make proteins — is defective in fragile X syndrome and most likely other autism spectrum disorders as well, according to a fruit fly study.
The study, “Fragile X mental retardation 1 gene enhances the translation of large autism-related proteins,” was published in Science.
Fragile X syndrome is the most frequent single genetic cause of autism spectrum disorder. Children with the condition often exhibit autism-like features, including impaired social skills, hyperactivity, and repetitive behaviors, along with intellectual and developmental disabilities, such as speech.
Fragile X is caused by mutations in the FMR1 gene, which provides instructions for making an RNA-binding protein, called FMR1, that influences mRNA translation. FMR1 is required for the development and function of the nervous system and ovaries in humans, mice, and fruit flies. Interestingly, both tissues store mRNAs thought to be regulated by FMR1, suggesting that this protein may have a specific function in controlling the production of proteins from stored mRNAs.
The genetic information of all living creatures is contained within DNA. But for this information to become functional, it first needs to be somehow transformed into functional proteins, a process known as translation. However, this process depends on certain important players capable of decoding the instructions contained within DNA. Among them is mRNA.
In this study, researchers aimed to investigate whether FMR1 could be involved in regulating the production of proteins from stored mRNAs in a physiological context. To this end, they analyzed quiescent fruit fly oocytes — eggs that are in a dormant state, before being fertilized by sperm — which rely heavily on the translation of stored mRNA, just like neural synapses in the brain.
First, researchers genetically engineered fruit flies to lack the FMR1 gene, mimicking human fragile X syndrome. They found that oocytes lacking FMR1 usually gave rise to embryos with severe neural defects, unlike those that retained FMR1.
“[D]isrupting FMR1 function while oocytes are fully dependent on translational regulation specifically compromised their ability to support neural development relative to controls,” the authors wrote.
Researchers then used a technique called ribosome profiling — a next-generation sequencing method that allows the determination of which specific mRNAs are being translated at a given moment — and found that FMR1 favors the translation of stored mRNAs that overlap with previously identified FMR1 targets, and acts mainly on larger proteins.
Remarkably, when investigators looked more closely at these targets and searched for the human gene correspondents, they found that at least 20 were associated with intellectual disability, while 30 others were involved in neurodevelopmental dysfunction.
“Because the challenges of translating large proteins are likely to increase in adult neurons under the influence of aging, the pathways and targets assayed here may contribute to adult-onset neural impairments such as schizophrenia and dementia,” the authors wrote.
These findings indicate that the production of multiple large proteins from stored mRNAs seems to be deeply affected in fragile X, and possibly other autism spectrum disorders as well.
“Small-molecule agents that counteract the tendency of large mRNAs to be segregated into inactive granules represent potentially valuable therapeutics,” the researchers said.