Study Unlocks Secrets of Autism

An essential link has been recognized between protein synthesis and autism spectrum disorder (ASD) by researchers from the McGill University and the University of Montreal. The researchers believe that this discovery will help support new therapeutic opportunities.

Autism Spectrum Disorder, a group of developmental disabilities can trigger significant social, communication and behavioral challenges. "Spectrum disorders" means ASD affects each person in different ways, and can range from very mild to severe.

About 1 in 88 children has been identified with an autism spectrum disorder (ASD) according to estimates from the Centre for Disease Control's Autism and Developmental Disabilities Monitoring (ADDM) Network. It is 5 times more common among boys (1 in 54) than girls.

Cells manufacture proteins by the regulation of protein synthesis. This is also known as mRNA translation. This mechanism is involved in all aspects of cell and organism function.

A new study conducted on a mice model noticed abnormally high synthesis of a group of neuronal proteins called neuroligins results in symptoms that are similar to those diagnosed in ASD.

In this study the researchers found autism-like behavior could be rectified in adult mice with compounds inhibiting protein synthesis, or gene therapy targeting neuroligins.

"My lab is dedicated to elucidating the role of dysregulated protein synthesis in cancer etiology. However, our team was surprised to discover that similar mechanisms may be implicated in the development of ASD," explained professor Nahum Sonenberg, from McGill's Dept. of Biochemistry, Faculty of Medicine and the Goodman Cancer Research Centre. "We used a mouse model in which a key gene controlling initiation of protein synthesis was deleted. In these mice, production of neuroligins was increased. Neuroligins are important for the formation and regulation of connections known as synapses between neuronal cells in the brain and essential for the maintenance of the balance in the transmission of information from neuron to neuron."

"Since the discovery of neuroligin mutations in individuals with ASD in 2003, the precise molecular mechanisms implicated remain unknown," said Christos Gkogkas, a postdoctoral fellow at McGill and lead author. "Our work is the first to link translational control of neuroligins with altered synaptic function and autism-like behaviors in mice. The key is that we achieved reversal of ASD-like symptoms in adult mice. Firstly, we used compounds, which were previously developed for cancer treatment to reduce protein synthesis. Secondly, we used non-replicating viruses as vehicles to put a break on exaggerated synthesis of neuroligins."

"By using a new sophisticated computer algorithm that we specially developed to answer Dr. Sonenberg's questions, we identified the unique structures of mRNAs of the neuroligins that could be responsible for their specific regulation," explained professor François Major of the University of Montreal's Institute for Research in Immunology and Cancer.

The researchers suggested that dysregulated synthesis of neuroligins expands synaptic activity. This results in an imbalance between excitation and inhibition in single brain cells thereby opening up exciting new opportunities for research that may unlock the secrets of autism.

"The autistic behaviors in mice were prevented by selectively reducing the synthesis of one type of neuroligin and reversing the changes in synaptic excitation in cells," explained professor Jean-Claude Lacaille at the University of Montreal's Groupe de Recherche sur le Système Nerveux Central and Department of Physiology. "In short, we manipulated mechanisms in brain cells and observed how they influence the behaviour of the animal."

The reversal of changes in inhibition and augmenting autistic behaviour was possible by manipulating a second neuroligin.

"The fact that the balance can be affected suggests that there could be a potential for pharmacological intervention by targeting these mechanisms," Lacaille concluded.

The results are published in the journal Nature.