![\"Illustration](\"https:\/\/scitechdaily.com\/images\/Illustration-of-Glutamate-Transport-in-Neural-Cells-777x437.jpg)
<\/p>\nIllustration of the glutamate transporter (pink) in neural cells (blue), with glutamate and anions in yellow and orange. Credit score: A. Guskov, College of Groningen<\/p>\n
<\/div>\n Episodic ataxia sort 6 is a uncommon neurological dysfunction that impacts solely a small variety of people globally. It results in short-term lack of muscle coordination and is brought on by a mutation that alters a single amino acid<\/span> in a protein responsible for transporting the neurotransmitter glutamate across neural cell membranes. Scientists from the University of Groningen in the Netherlands have uncovered the mechanism by which this mutation causes malfunction in these cells. Their findings were recently published in the journal Nature Communications<\/span><\/em>.<\/p>\n Individuals suffering from ataxia experience a loss of muscle control, which can result in difficulties with movements and speech. Among the various forms of ataxia, episodic ataxia type 6 (EA6) is a particularly rare condition, characterized by episodes of muscle control loss. Currently, only a small number of individuals, including one family in the Netherlands, have been identified as having EA6 worldwide, with the total number of known patients numbering just over a dozen.<\/p>\n <\/span><\/p>\n Professor Albert Guskov, lead author of the paper in Nature Communications on the effect of a single mutation in a glutamate transport protein in neural cells. This mutation causes the neurological disease Episodic Ataxia type 6. Credit: University of Groningen<\/p>\n<\/div>\n It is known that EA6 is caused by a single mutation, but how this mutation can have such a dramatic effect was thus far a mystery. \u2018This protein transports glutamate across the membrane of neural cells,\u2019 explains structural biologist Albert Guskov. The protein is inserted in the cell membrane, and the mutation changes a proline amino acid in one of the helical transmembrane domains into an arginine.<\/p>\n \u201cA proline in a helix typically causes a kink,\u201d explains Guskov. \u201cIf a proline is changed into an arginine, we would expect this kink to disappear. To test this, we studied the structure of the mutated protein.\u201d<\/p>\n <\/span><\/p>\n Since the human transport protein is difficult to study in the lab, Guskov and his colleagues used an analogous protein from archaea, an ancient form of unicellular organism.<\/p>\n \u201cThis archaeal protein has been well conserved throughout evolution, and we know from previous work that it is a good model for the human transport protein, even though it transports aspartate and not glutamate,\u201d explains Guskov.<\/p>\n Using cryo-electron microscopy on normal and mutated proteins placed in lipid nanodiscs, the team was able to compare the shape of the mutated protein to the normal version. In previous studies, the team had shown that part of the protein moves up and down through the membrane, much like an elevator. The hypothesis was that the mutation would cause the transmembrane kink in the protein to disappear, and that this would change the protein\u2019s shape and block the elevator movement.<\/p>\n However, that was not the case. Guskov: \u201cTo our surprise, the kink was still there.\u201d<\/p>\n <\/span><\/p>\n Nevertheless, the mutation did affect the functioning of the protein. \u201cThe transport rate was reduced by a factor of two, compared to the normal protein.\u201d Furthermore, during the transport of the aspartate, the protein transiently formed an anion channel. \u201cAnd in the mutated protein, ion transport was three times higher.\u201d<\/p>\n Somehow, the arginine that replaced the proline did not alter the shape of the transport protein, but it did affect its function. Therefore, the researchers performed molecular dynamics simulations, which show all the interactions of the amino acids<\/span> of the protein with their surroundings. \u201cWhat we noticed is that a salt bridge is formed between the arginine amino acid and the lipids of the membrane.\u201d This salt bridge, a form of attraction between molecules, appears to slow down the movement of the elevator part of the protein.<\/p>\n Guskov: \u201cIf this elevator moves more slowly, it explains the decrease in aspartate transport, but it also means the transient ion channel remains open longer, thus enabling more anions to pass through.\u201d In human neural cells, this would lead to a reduced transport of the neurotransmitter glutamate, and increased anion imbalance. These findings explain how this mutation causes ataxia. \u201cBoth have very nasty consequences for the functioning of neural cells.\u201d<\/p>\n However, there is no simple way to remedy the effect of the mutation. Guskov: \u201cFurthermore, this transporter is present throughout the body, so any drug affecting it will probably have serious side effects.\u201d Also, since there are only a handful of patients, no drug company would invest in a cure. \u201cAlthough there might be a lot more patients. Since it is an episodic illness and the symptoms can be mild, many people might not be aware of it. They are simply used to feeling unwell for a few days at a time, just like someone who suffers from migraine.\u201d<\/p>\n![\"Albert](\"https:\/\/scitechdaily.com\/images\/Albert-Guskov.jpg)
<\/p>\nSurprise<\/h4>\n
Nasty consequences<\/h4>\n
Questions<\/h4>\n