Summary: Researchers report almost one thrid of all autism cases could be the result of a scarcity of nSR100, a protein important for brain development.
Source: University of Toronto.
One protein’s sweeping influence on the development of autism revealed.
As many as a third of autism cases could be explained by a scarcity of a single protein in the brain, Toronto scientists have revealed. The findings provide a unique opportunity to develop treatments for a disorder that is rooted in a motley crew of genetic faults.
Researchers induced autistic-like behaviour in mice by lowering the levels of a protein called nSR100 (also known as SRRM4), which is important for normal brain development. The study, published in the December 15 issue of the journal Molecular Cell, builds on the teams’ previous work which showed that the nSR100 protein was reduced in the brains of autistic people.
The teams were led by Professors Benjamin Blencowe of the University of Toronto’s Donnelly Centre and Sabine Cordes of the Department of Molecular Genetics and Sinai Health System’s Lunenfeld-Tanenbaum Research Institute.
“We previously reported an association between nSR100 protein levels and autism. But this time we show that reduced levels of this protein could really be causative–that’s a big deal. Just by reducing the nSR100 levels by 50 per cent, we observe hallmarks of autistic behaviour,” said Cordes.
The data also suggest that nSR100 acts as a hub that channels diverse molecular miscues which contribute to autism.
Known best for altered social behaviours, the degree of which can vary tremendously, autism is a common neurological disorder affecting more than one per cent of the population. While its origins are genetic, the specific causes are known in only a fraction of cases that fall into the autism spectrum disorder (ASD). For the majority of people diagnosed with ASD, the reasons behind their disorder remain unknown.
The U of T study provides evidence for the sweeping influence that nSR100 protein has on social behaviour and other features of autism. In the brain, nSR100 acts as a key regulator of alternative splicing–a process that generates a remarkable diversity of proteins, the building blocks of cells.
Proteins are encoded in the DNA sequence of the genes, but the useful instructions are broken up and separated by non-coding DNA. During alternative splicing, non-coding spacers are spliced out and protein-coding segments are brought together to make a finished protein template. But the order in which the coding instructions are stitched together can change so that a single gene can spawn a variety of proteins. This way, cells can expand their protein toolbox to vastly outstrip the number of genes. It’s no surprise then, that alternative splicing is especially pronounced in the brain, where the mushrooming protein diversity is thought to be the driving force behind the brain’s astonishing complexity.
Blencowe’s team previously discovered nSR100 and had shown that it is diminished in the brains of many autistic people. This finding suggested that autism could, in part, stem from an accumulation of incorrectly spliced proteins in brain cells. This could then lead to mistakes in brain wiring and autistic behaviour further down the road.
This time, the teams decided to test head-on if nSR100 scarcity can indeed cause autism. To do this, Mathieu Quesnel-Vallieres, a graduate student jointly supervised by Blencowe and Cordes, created a mutant mouse that lacks nSR100 in order to study its behaviour.
The researchers were amazed to find that reducing nSR100 protein levels only by half was enough to trigger the behavioural hallmarks of autism, including avoidance of socialinteractions and heightened sensitivity to noise. The nSR100 mutant mice also shared many other features of autism with human patients, such as changes in alternative splicing and brain wiring.
Working with graduate student Zahra Dargaei and Professor Melanie Woodin in the Department of Cell and Systems Biology at the University of Toronto, and with Dr. Manuel Irimia at the Centre for Genomic Regulation in Barcelona, the researchers were also able to show that nSR100 levels are linked to neuronal activity. “If you have an increase in neuronal activity, which is the case in many forms of autism, the nSR100-controlled alternative splicing program is disrupted and this likely underlies autistic behaviour,” said Quesnel-Vallieres.
“A major value of the nSR100 deficient mouse is that it can explain other causes of autism and how they impact neurobiology by converging on the nSR100 protein”, said Blencowe who is also a Professor in U of T’s Department of Molecular Genetics. “Our mouse model will also serve as a useful testing ground for small molecules that have potential to reverse nSR100 deficiency in autism,” he added.
“Instead of focusing on individual mutations linked to autism, it’s much more powerful to identify regulatory hubs like nSR100. In the future, if you turned this protein up a little bit in autistic patients, you might be able to improve some of the behavioural deficits” said Cordes.
Funding: Funding provided by Canadian Institute for Health and Research, European Research Council Starting Grant.
Source: Jovana Drinjakovic – University of Toronto
Image Source: NeuroscienceNews.com image is adapted from the UofTMed video.
Video Source: The video is credited to UofTMed.
Original Research: Abstract for “Misregulation of an Activity-Dependent Splicing Network as a Common Mechanism Underlying Autism Spectrum Disorders” by Mathieu Quesnel-Vallières, Zahra Dargaei, Manuel Irimia, Thomas Gonatopoulos-Pournatzis, Joanna Y. Ip, Mingkun Wu, Timothy Sterne-Weiler, Shinichi Nakagawa, Melanie A. Woodin, Benjamin J. Blencowe, and Sabine P. Cordes in Molecular Cell. Published online November 22 2016 doi:10.1016/j.molcel.2016.11.033
Misregulation of an Activity-Dependent Splicing Network as a Common Mechanism Underlying Autism Spectrum Disorders
•Multiple autistic-like features in nSR100/Srrm4 haploinsufficient mice
•nSR100 mutant mice have altered synaptic transmission and neuronal excitability
•Neuronal activation induces splicing changes observed in autistic individuals
•Neuronal activation alters splicing by reducing nSR100 levels
A key challenge in understanding and ultimately treating autism is to identify common molecular mechanisms underlying this genetically heterogeneous disorder. Transcriptomic profiling of autistic brains has revealed correlated misregulation of the neuronal splicing regulator nSR100/SRRM4 and its target microexon splicing program in more than one-third of analyzed individuals. To investigate whether nSR100 misregulation is causally linked to autism, we generated mutant mice with reduced levels of this protein and its target splicing program. Remarkably, these mice display multiple autistic-like features, including altered social behaviors, synaptic density, and signaling. Moreover, increased neuronal activity, which is often associated with autism, results in a rapid decrease in nSR100 and splicing of microexons that significantly overlap those misregulated in autistic brains. Collectively, our results provide evidence that misregulation of an nSR100-dependent splicing network controlled by changes in neuronal activity is causally linked to a substantial fraction of autism cases.
“Misregulation of an Activity-Dependent Splicing Network as a Common Mechanism Underlying Autism Spectrum Disorders” by Mathieu Quesnel-Vallières, Zahra Dargaei, Manuel Irimia, Thomas Gonatopoulos-Pournatzis, Joanna Y. Ip, Mingkun Wu, Timothy Sterne-Weiler, Shinichi Nakagawa, Melanie A. Woodin, Benjamin J. Blencowe, and Sabine P. Cordes in Molecular Cell. Published online November 22 2016 doi:10.1016/j.molcel.2016.11.033