Summary of How a Single Mutation Causes a Devastating Neurological Disease:
Scientists from the University of Groningen have uncovered the mechanism behind episodic ataxia type 6, a rare neurological disorder caused by a single mutation that alters the protein responsible for transporting the neurotransmitter glutamate across neural cell membranes. Using cryo-electron microscopy on an analog protein from archaea, the team found that the mutation did not alter the shape, but rather the functioning, of the protein, leading to reduced transport of glutamate and increased anion imbalance. The mutation causes temporary loss of muscle coordination, but there is no simple way to remedy its effect, and any drug affecting it is likely to have serious side effects.
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New Study Sheds Light on Rare Neurological Disorder
Episodic ataxia type 6 is a rare neurological disorder that causes temporary loss of muscle coordination. A single mutation causes it, but until recently, scientists did not understand how it caused such a dramatic effect. However, researchers from the University of Groningen in the Netherlands have uncovered the mechanism behind the disorder.
What is Episodic Ataxia Type 6?
Episodic ataxia type 6 is a rare neurological disorder that causes temporary loss of muscle coordination. It affects only a small number of individuals globally, and until recently, the mechanism of the condition was unknown.
The Mechanism Behind Episodic Ataxia Type 6
Scientists from the University of Groningen in the Netherlands studied the mechanism behind the disorder. They discovered that a mutation in a protein responsible for transporting the neurotransmitter glutamate across neural cell membranes causes the malfunction in these cells.
Understanding the Protein
The protein transporting the neurotransmitter glutamate across neural cell membranes is inserted into the cell membrane. The mutation changes a proline amino acid in one of the helical transmembrane domains into an arginine. Typically, a proline in a helix causes a kink, which should disappear if changed into arginine. Scientists examined the structure of the mutated protein to test this theory.
Using cryo-electron microscopy, the team compared the shape of the mutated protein to the standard version by studying the proteins placed in lipid nanodiscs. During the transport of the amino acid aspartate, the protein transiently formed an anion channel, which resulted in ion transport three times higher than the standard protein.
The Findings
The researchers found that the mutation did not affect the shape of the transport protein, but it did affect its function. A salt bridge formed between the arginine amino acid and the membrane’s lipids, which slowed down the movement of the elevator part of the protein. Consequently, the transient ion channel remained open longer, enabling more anions to pass through. In human neural cells, this would cause a reduced transport of the neurotransmitter glutamate and an increased anion imbalance. These findings explain how this mutation causes ataxia.
Implications for Patients
Unfortunately, there is no simple way to remedy the effect of the mutation. The transporter is present throughout the body, so any drug that affects it will likely have serious side effects. Since there are only a handful of patients globally, no drug company would probably invest in a cure.
Implications for Science
For the scientific community, these findings raise several intriguing questions. As the protein has been very well conserved throughout evolutionary history, scientists are interested in understanding why the transient anion channel appeared and why it was carried over time to our neurons.
Conclusion
Episodic ataxia type 6 is a rare neurological disorder that causes temporary loss of muscle coordination. Until recently, scientists did not understand how the condition was caused. However, researchers from the University of Groningen in the Netherlands discovered that a mutation in a protein responsible for transporting the neurotransmitter glutamate across neural cell membranes causes the malfunction. The modification did not affect the shape of the transport protein, but it did affect its function by slowing down the movement of the elevator part of the protein. Unfortunately, there is no simple remedy for the effect of the mutation. Since there are only a handful of patients globally, it is unlikely that any drug company will invest in a cure.
