| A team of researchers led by Nahum Sonenberg of McGill University has created a new model of mouse autism, and then reversed its symptoms. They began by genetically engineering mice so that they lacked a certain gene. The researchers are optimistic that the findings can help identify some of the key gateways in autism spectrum disorder. |
Autism spectrum disorders (ASD) encompass a wide array of neurodevelopmental diseases that affect three areas of behaviour: social interactions, communication and repetitive interests or behaviors. According to the U.S.-based Centers for Disease Control and Prevention, 1 in 88 children suffer from ASD, and the disorder is reported to occur in all racial, ethnic, and socioeconomic groups. ASDs are almost five times more common among boys (1 in 54) than among girls (1 in 252).
Regulation of protein synthesis, also termed mRNA translation, is the process by which cells manufacture proteins. This mechanism is involved in all aspects of cell and organism function.
Now, a new study in mice has found that abnormally high synthesis of a group of neuronal proteins called neuroligins results in symptoms similar to those diagnosed in ASD.
They began by genetically engineering mice so that they lacked the gene Eif4ebp2. The 4E-BP2 protein that this produces suppresses the translation of certain messenger RNAs, so knocking out Eif4ebp2 allows the proteins that these mRNAs produce to be synthesized at above normal levels.
Mice lacking Eif4ebp2 exhibit many autism-like symptoms, including poor social interaction, altered communication and repetitive behaviours. Sonenberg and his team found that one group of proteins that proliferates in the absence of Eif4ebp2 is the neuroligins (NLGNs), which sit in the membrane of neurons and help to create and maintain the connections, or synapses, between nerve cells.
The study also shows that autism-like behaviors can be rectified in adult mice with compounds inhibiting protein synthesis, or with gene therapy targeting neuroligins. Their results are published in the journal Nature.
“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 Prof. 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.”
Computer modeling played an important role in this research. “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 Prof. François Major, of the University of Montreal’s Institute for Research in Immunology and Cancer and Department of Computer Science.
The researchers found that dysregulated synthesis of neuroligins augments synaptic activity, resulting in an imbalance between excitation and inhibition in single brain cells, opening up exciting new avenues for research that may unlock the secrets of autism.“The autistic behaviours in mice were prevented by selectively reducing the synthesis of one type of neuroligin and reversing the changes in synaptic excitation in cells,” explained Prof. Jean-Claude Lacaille at the University of Montreal’s Groupe de Recherche sur le Système Nerveux Central and Department of Physiology.
Despite these results, Sonenberg cautions against interpreting them as a sign that a treatment for ASD is around the corner. “The drug we used would be too toxic to use for ASDs,” he says. “But we’ve shown that this pathway is important, identified potential therapeutic targets and demonstrated that a drug therapy is possible in principle.”
The search for drug therapies is complicated by the fact that ASD has many genetic causes. Nonetheless, Sonenberg says, it’s possible that these diverse mutations could converge on the same pathway — which Price describes as an interesting “unifying hypothesis”.
“This is extremely important idea to test,” Sonenberg adds, “and it’s something we’re researching now.”
SOURCE Science Daily, Nature News
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