nSR100 protein's influence on autism
As many as a third of autism cases could be explained by a scarcity of a single protein in the brain. These findings from research at the University of Toronto are an autism breakthrough. They provide a unique opportunity to develop treatments for a disorder that is rooted in a motley crew of genetic faults.
University of Toronto (U of T) research induced autistic-like behaviour in mice by lowering the levels of a protein called nSR100. The work was led by Benjamin Blencowe PhD of the Donnelly Centre and Sabine Cordes PhD in the Department of Molecular Genetics and Sinai Health System's Lunenfeld-Tanenbaum Research Institute.
nSR100 (also known as SRRM4) is important to normal brain development. The study builds on the teams' previous work showing that the nSR100 protein was reduced in the brains of autistic people. The data also suggests that nSR100 acts as a hub that channels diverse molecular miscues which contribute to autism.
The current work is published in the December 15, 2016 issue of the journal Molecular Cell.
"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."
Sabine P. Cordes PhD, Professor, Department of Molecular Genetics, University of Toronto, Toronto, Canada; and
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
Known best for altered social behaviours of tremendously varying degrees, autism is a common neurological disorder affecting more than one per cent of the population. While its origins are genetic, specific causes are known in only a fraction of cases. For the majority of people diagnosed with autism spectrum disorder (ASD), the reasons behind their disorder remains unknown.
The U of T study provides evidence for the sweeping influence 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, those building blocks of cells.
Proteins are encoded in the DNA of genes, but 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 coding instructions are stitched together can change so that a single gene can spawn a variety of proteins. It is a process of gene expression (function) which results in a single gene coding for multiple proteins.
In alternative splicing, cells expand their protein toolbox to outstrip their limited number of genes. Alternative splicing is especially pronounced in the brain, where expanding protein diversity is thought to drive the brain's complexity.
Benjamin Blencowe's team previously discovered nSR100 and shown it is diminished in the brains of many autistic people. His finding suggests that autism could, in part, stem from an accumulation of incorrectly spliced proteins in brain cells. This could lead to mistakes in brain wiring and autistic behaviour further down the road.
In the most recent experiments, the teams decided to test if nSR100 scarcity can indeed cause autism. To do so, Mathieu Quesnel-Vallieres, graduate student jointly supervised by Blencowe and Cordes, created a mutant mouse lacking nSR100 to study its behaviour.
Researchers were amazed to find reducing nSR100 protein levels by half was enough to trigger behavioural hallmarks of autism — including social-avoidance and heightened sensitivity to noise. The nSR100 mutant mice also displayed other features of autism with human patients — changes in alternative splicing and brain wiring.
"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. Our mouse model will also serve as a useful testing ground for small molecules that have potential to reverse nSR100 deficiency in autism," adds Benjamin J. Blencowe PhD, Professor,
Department of Molecular Genetics, and Donnelly Centre, University of Toronto, Toronto, Canada.
Explains Cordes:"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."
•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.
autism spectrum disorder, alternative splicing, microexons, nSR100/SRRM4, neuronal activity
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