Several diseases within the autistic spectrum are often linked to genetic mutations that affect protein synthesis in neurons. An example of this type of disease , affecting as many as 1 in 4000 males and 1 in 6000 females in the UK alone, is the so called fragile X syndrome. Mutations in the FMR1 gene, responsible for encoding a protein called FMRP, are often a single-gene cause of this disorder.
FMRP is produced at the hippocampal synapses by glutamate receptors. This protein inhibits messenger RNA (mRNA) translation, inhibiting protein synthesis. In mice when the FMR1 gene is mutated, the loss of FMRP leads to excessive protein synthesis. Such a condition is often associated with neurological pathologies in the fragile X syndrome.
Excessive translation of mRNAs, leading to excessive protein production, can occur due to a defect in inhibiting this process (mediated by FMR1 mutations leading to loss of FMRP activity) or due to mistranslation of certain mRNAs, the causes of which are currently unknown. While many studies have addressed which mRNAs are targeted by FMRP itself, few studies have paid attention to which mRNAs are mistranslated in general.
In a study led by Dr. Emily Osterweil of the Centre for Integrative Physiology at the University of Edinburgh, Dr. Sophie Thomson and colleagues aimed to identify mRNAs that translate differentially in the CA1 pyramidal hippocampal neurons of the mouse model for fragile X syndrome lacking FMR1 gene. Of 121 such candidates, they found Chrm4, encoding a subtype of the muscarinic acetyl choline receptor called M4, to be significantly overexpressed in mice with fragile X syndrome. Intuitively, inhibiting M4 should then contribute to correction of the pathology observed in these mice. On the contrary, the team observed that enhancing M4 with a highly specific allosteric modulator that mimics M4 normalises the excessive protein translation and also reduces the incidences of audiogenic seizures. These results suggest that not all mistranslated mRNAs contribute to pathological changes observed in the fragile X syndrome.
Whether M4 overexpression could be a potential natural mechanism to try and compensate for the pathology observed is still an open question. This only serves to reinstate the fact that we have a long way to go in understanding how single gene mutations can lead to widespread effects and be the cause of complex autistic disorders
This article was written by Aishwarya Sivakumar and edited by James Hitchen.
