How `flawed` transport gene contributes to autism

Washington: Researchers have said that mutations in an autism-linked gene, dubbed NHE9, involved in transporting substances in and out of structures within the cell, causes communication problems among brain cells that may contribute to the disease's development.

For the new study, Rajini Rao, Ph.D., a professor of physiology in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine, and her collaborators focused on NHE9, which other researchers had flagged as a suspect in attention-deficit hyperactivity disorder, addiction and epilepsy as well as autism spectrum disorders.

Rao's collaborators at Tel Aviv University and Technion-Israel Institute of Technology constructed a computer model of the NHE9 protein based on previous research on a distant relative in bacteria.

They then used the model to predict how autism-linked variants in the NHE9 gene would affect the protein's shape and function. Some of them were predicted to cause dramatic changes, while other changes appeared to be more subtle.

Rao's team next tested how these variant forms of NHE9 would affect a relatively simple organism often used in genetic studies: yeast.

To do that, the team engineered the yeast form of NHE9 to have the variants seen in autistic people.

For those mutations that did have a detectable effect on the yeast, the team moved on to a third and more challenging step, in mouse brains.

They homed in on astrocytes, a type of brain cell that clears the signaling molecule glutamate out of the way after it has performed its job of delivering a message across a synapse between two nerve cells. Using lab-grown mouse astrocytes with variant forms of NHE9, the researchers found a change in the pH (acidity) inside cellular compartments called endosomes, which in turn altered the ability of cells to take up glutamate.

Rao said that because endosomes are the vehicles that deliver cargo essential for communication between brain cells, changing their pH alters traffic to and from the cell surface, which could affect learning and memory.

The study has been published in journal Nature Communications.



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