One protein's sweeping influence on the development of autism revealed

December 15, 2016, University of Toronto
Reducing nSR100 protein levels by half was enough to trigger autistic-like behavior in these animals. Credit: Mathieu Quesnel Vallieres

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 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 (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 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 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 , 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.

Explore further: Mighty microexons take center stage in shaping of the brain

More information: Molecular Cell, DOI: 10.1016/j.molcel.2016.11.033 , http://www.cell.com/molecular-cell/fulltext/S1097-2765(16)30806-1

Related Stories

Mighty microexons take center stage in shaping of the brain

April 1, 2015
Complex brain disorders, such as autism or schizophrenia, still puzzle scientists because their causes lie hidden in early events of brain development, which are still poorly understood. This is about to change thanks to ...

Scientists discover tiny gene fragments linked to brain development and autism

December 18, 2014
Very small segments of genes called "microexons" influence how proteins interact with each other in the nervous system, scientists at the University of Toronto have found, opening up a new line of research into the cause ...

Zinc found to reverse brain cell changes in autism

August 31, 2016
Cellular changes in the brain caused by genetic mutations that occur in autism can be reversed by zinc, according to research at the University of Auckland.

Splice variants reveal connections among autism genes

April 11, 2014
A team of researchers from the University of California, San Diego School of Medicine and the Center for Cancer Systems Biology (CCSB) at the Dana-Farber Cancer Institute has uncovered a new aspect of autism, revealing that ...

Novel mouse model sheds new light on autism spectrum disorder

June 1, 2016
A new mouse model, developed by researchers at the University of Wisconsin-Madison, is the first to show that when more of a specific biological molecule moves between different parts of nerve cells in the mouse brain, it ...

Recommended for you

Genes contribute to biological motion perception and its covariation with autistic traits

January 22, 2018
Humans can readily perceive and recognize the movements of a living creature, based solely on a few point-lights tracking the motion of the major joints. Such exquisite sensitivity to biological motion (BM) signals is essential ...

Nearly imperceptible fluctuations in movement correspond to autism diagnoses

January 17, 2018
A new study led by researchers at Indiana University and Rutgers University provides the strongest evidence yet that nearly imperceptible changes in how people move can be used to diagnose neurodevelopmental disorders, including ...

Epigenetics study helps focus search for autism risk factors

January 16, 2018
Scientists have long tried to pin down the causes of autism spectrum disorder. Recent studies have expanded the search for genetic links from identifying genes toward epigenetics, the study of factors that control gene expression ...

Being bilingual may help autistic children

January 16, 2018
Children with Autism Spectrum Disorders (ASD) often have a hard time switching gears from one task to another. But being bilingual may actually make it a bit easier for them to do so, according to a new study which was recently ...

No rise in autism in US in past three years: study

January 2, 2018
After more than a decade of steady increases in the rate of children diagnosed with autism in the United States, the rate has plateaued in the past three years, researchers said Tuesday.

Autism therapy: Brain stimulation restores social behavior in mice

December 13, 2017
Scientists are examining the feasibility of treating autistic children with neuromodulation after a new study showed social impairments can be corrected by brain stimulation.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.