Newly identified mutations in SCA19/22 and their dysfunctions

Written by Sophia Leung Edited by Dr. Marija Cvetanovic

While the mutant proteins in SCA19/22 lose part of their innate functions and properties, they also disrupt the key functions of the normal healthy protein.

The underlying mechanism of the hereditary property of SCA19/22 is elusive. In this study, the researchers investigated the molecular properties of four different mutations found in patients with SCA19/22. They looked at how these mutant proteins affect the normal protein if they are both present in the cell. They found that the mutant proteins are not only non-functional (do not work properly), but that in their presence, the normal protein’s function is also diminished. Furthermore, while the production and proper localization of these mutant proteins are found to be defective, they also bring the same decline to the normal protein. This adds to their disease-causing properties. This study is significant in that it offers a molecular investigation into mutant proteins associated with SCA19/22 that was previously lacking. It also provides evidence that may explain the hereditary property of the disease.

A number of mutations in the gene KCND3 has been associated with SCA19/22. The gene makes the voltage‐gated potassium ion (K+) channel subunit KV4.3. In general terms, the gene makes a protein that functions to allow potassium ions to pass through the membrane of nerve cells. Similar to how a flute has many holes to allow air to pass through when played to make a specific note, a nerve cell has different kinds of channels to allow ions to pass through their membrane to orchestrate normal functioning. One could imagine the disruption to any channels, a partial obstruction or a total blockage, could perturb the overall output of the cell.

flute resting on a music stand
Similar to how a flute has many holes to allow air to pass through when played to make a specific note, a nerve cell has different kinds of channels to allow ions to pass through to orchestrate normal functioning. (Photo by Rajesh Kavasseri / Unsplash)

In this study, the researchers found that the normal KV4.3 channel protein detectably allows potassium ions to pass through. But little to no ions can pass through the SCA19/22 mutant KV4.3 channels. Even under the assistance of a “helper” protein, which normally enhances the function of this channel, only one of the mutant channel proteins shows improvement. This indicates that the SCA19/22 causing mutations result in a reduced function of mutated KV4.3 channels.

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Snapshot: What is an ion channel?

One of the most important features of neurons (Purkinje cells, for example), is that they are capable of electrical communication. Think of the last time you saw a TV intro or movie montage with a depiction of the brain on a microscopic level – though it’s technically invisible to the naked eye, that ‘spark’ you can see traveling down a portion of the neuron is actually not too far from reality. One of the most common ways to describe an active neuron, in fact, is to say that it’s “firing.” Essentially, when a neuron is activated, it ‘fires off’ an electrical impulse that is transmitted down a long, slender extension known as the axon. The axon ends where the next neuron in the circuit begins, and when the impulse arrives at that point, it initiates a series of events that allows the signal to jump to the next cell.

cartoon of neuron delivering an electrical impulse
An electrical impulse traveling down a neuron. Photo courtesy of Wikimedia.

This electrical signal is made possible by molecular machines known as ion channels. These proteins span the cell membrane, which is the barrier between the interior and exterior of the cell. When they receive a certain signal, the channel opens, allowing ions – atoms that carry an electrical charge, such as sodium, potassium, and calcium – to pass through. There are many types of proteins that allow the transport of small molecular components, but the source of a neuron’s electrical capabilities is that its channels specifically allow ions to pass into or out of the cell. Though a single ion’s charge is quite small, the large number of ions that are exchanged when a neuron’s channels open makes for a significant electrical effect – enough to produce an electrical signal that allows neurons to communicate with one another, giving us the ability to think, move, and interact with our environment.

diagram of an ion channgel in the closed, open, and inactivated state.
Cartoon of an ion channel in different states. Photo courtesy of Wikimedia.

Though the mutations that cause SCAs typically occur in genes that are expressed in every cell of the body, disease is usually restricted to the brain. One theory about why this is the case is that these SCA-related genes are necessary for the health and maintenance of ion channels in certain brain tissues – namely, the cerebellum and brainstem. At any rate, there is evidence that the electrical activity of these brain regions is abnormal in many SCAs, which strongly suggests that ion channels play a critical role in these disorders.

If you would like to learn more about ion channels, take a look at this Encyclopaedia Britannica article.

Snapshot written by Logan Morrison edited by Dr. David Bushart