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A new theory for autism that may underpin up to a third of cases given support from a new mouse model

December 15, 2016

 

  nSR100 mutant mouse. Reducing nSR100 protein levels by half was enough to trigger autistic-like behaviour. (Credit: Mathieu Quesnel-Vallieres )
  nSR100 mutant mouse. Reducing nSR100 protein levels by half was enough to trigger autistic-like behaviour.
(Credit: Mathieu Quesnel-Vallieres)
                                                       
click the image for a larger version

By Jovana Drinjakovic

Over the past decade, there has been enormous progress in understanding the effect of genes on autism spectrum disorder (ASD). Indeed, through DNA sequencing technologies, a substantive list of genes that are associated with the disorder has been constructed. However, the vast majority of these affect a very small number of people. This presents a challenge in developing possible therapeutics. That may be about to change via a new study in mice by two teams of Toronto researchers who have found that as many as a third of autism cases could be explained by low levels of a single protein in the brain.

The researchers found that lowering the levels of a protein called nSR100 (also known as SRRM4) which is important for normal brain development, the mice developed autistic-like behaviours. The study, published in the December 15 issue of the journal Molecular Cell, builds on the teams’ previous work which showed that nSR100 protein is reduced in the brains of people with autism.

The teams were led by Professors Benjamin Blencowe of the University of Toronto’s Donnelly Centre and Sabine Cordes and Sinai Health System’s Lunenfeld-Tanenbaum Research Institute. Both researchers are members of the Department of Molecular Genetics.

“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 nSR100 levels by 50 per cent, we observe hallmarks of autistic behaviour,” said Cordes.

 
The Three-Chamber Experiment
                                               
click here to see it on YouTube
 
Their experimental findings 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 affects 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 ASD. For the majority of people diagnosed with ASD, the reasons behind their disorder remain unknown.

The new 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 genes, but the useful instructions are broken up and separated by segments of DNA that do not contribute to the instructions for making the actual protein. During alternative splicing, these gap regions of DNA are precisely edited out and protein-coding segments are stitched together to yield the template for a finished protein. 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, leading to autistic behaviour.

Based on their association data, the teams decided to test head-on whether nSR100 scarcity can in fact cause autism rather than be a possible bystander. To do this, Mathieu Quesnel-Vallieres, a graduate student jointly supervised by Blencowe and Cordes, created a strain fo mutant mice that lack nSR100 and then studied their behaviour compared to “normal” mice.


Three-chamber non-invasive behavioural testing apparatus
 
3-chamber non-invasive testing apparatus
 
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 social
interactions and heightened sensitivity to noise. The nSR100 mutant mice also shared many other molecular features of autism observed in 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 may 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 new drugs that have potential to reverse nSR100 deficiency in autism,” he added.

“Instead of focusing on individually rare mutations linked to autism, it’s much more powerful to identify regulatory hubs like nSR100. In the future, if you could turn this protein up a little bit in patients with autism, it may be able to improve some of the behavioural challenges” said Cordes. The research also offers a new way of thinking about the development of ASD. It needs to be noted, however, that the researchers do not yet know whether the effects of low nSR100 in patients are reversible.

 

Ref.: 
The study: http://www.cell.com/molecular-cell/fulltext/S1097-2765(16)30806-1
Video of the Three-Chamber Experiment on YouTube: www.youtube.com/watch?v=UPOb9swY4MQ
An article in the Globe and Mail, Technology-Science: theglobeandmail.com/technology/science/introverted-mice-reveal-clues-to-large-swath-of-autism-cases/article33343497/ 
Related previous work: http://www.sciencedirect.com/science/article/pii/S0092867414015128 

 

 

 

 

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