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New hope for understanding autism spectrum disorders
Researchers at 平特五不中 and the University of Montreal uncover a crucial link between protein synthesis and autism spectrum disorders
Researchers from 平特五不中 and the University of Montreal have identified a crucial link between protein synthesis and autism spectrum disorders (ASD), which can bolster new therapeutic avenues. 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. 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. The study also reveals 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听Nature.
Published: 21 November 2012
鈥淢y 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鈥�, explained Prof. Nahum Sonenberg, from 平特五不中鈥檚 Dept. of Biochemistry, Faculty of Medicine, and the Goodman Cancer Research Centre. 鈥淲e 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.鈥�
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鈥淪ince the discovery of neuroligin mutations in individuals with ASD in 2003, the precise molecular mechanisms implicated remain unknown,鈥� said Christos Gkogkas, a postdoctoral fellow at 平特五不中 and lead author. 鈥淥ur 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.鈥�
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Computer modeling played an important role in this research. 鈥淏y 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,鈥� explained Prof. Fran莽ois Major, of the University of Montreal鈥檚 Institute for Research in Immunology and Cancer and Department of Computer Science.
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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.
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鈥淭he 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,鈥� explained Prof. Jean-Claude Lacaille at the University of Montreal鈥檚听Groupe de Recherche sur le Syst猫me Nerveux Central听and Department of Physiology. 鈥淚n short, we manipulated mechanisms in brain cells and observed how they influence the behaviour of the animal.鈥� The researchers were also able to reverse changes in inhibition and augment autistic behaviors by manipulating a second neuroligin. 鈥淭he fact that the balance can be affected suggests that there could be a potential for pharmacological intervention by targeting these mechanisms,鈥� Lacaille concluded.
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About this study:
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This work is funded by grants from the Canadian Institutes of Health Research (CIHR), the Autism Speaks Agency and听the Fonds de la recherche du Qu茅bec 鈥� Sant茅.听Prof. Lacaille holds the Canada Research Chair in Cellular and Molecular Neurophysiology.听The University of Montreal is officially known as Universit茅 de Montr茅al.
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Links:
- 平特五不中:听
- Universit茅 de Montr茅al:听
- Nahum Sonenberg:听
- Jean-Claude Lacaille:听