Researchers make Autism breakthrough

Credit: Cell

As many as a third of autism cases could be explained by a scarcity of a single protein in the brain, a recent study has 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 /SRRM4 (neural- specific Ser/Arg repeat- related protein of 100kDa/ Ser/Arg Repetitive Matrix 4), which is important for normal brain development.

"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 the professor who lead the study.

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 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.

The team has 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, a graduate student, supervised by senior professors of the study, 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 social interactions 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.

In a collaborative work with researchers at Canada and Spain, the researchers were also able to to show that nSR100 levels are linked to neuronal activity. If there arises 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. “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 a senior professor of the study. "Our mouse model will also serve as a useful testing ground for small molecules that have potential to reverse nSR100 deficiency in autism”.

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.

http://www.cell.com/molecular-cell/fulltext/S1097-2765(16)30806-1

http://medicine.utoronto.ca/news/u-t-researchers-make-autism-breakthrough
 

Edited January 5th 2017