Mutated ataxin-1 protein forms harmful, doughnut-shaped aggregates that are not easily destroyed

Written by Brenda Toscano Marquez   Edited by Marija Cvetanovic

Insoluble clumps of mutated ataxin-1 capture essential proteins and trigger the creation of toxic reactive oxygen species.

All proteins produced by our cells consist of long chains of amino acids that are coiled and bent into a particular 3D structure. Changes in that structure can cause serious issues in a cell’s function, sometimes resulting in disease. Spinocerebellar ataxia type 1 (SCA1) is thought to be the result of one such structural change. The cause of SCA1 is a mutation that makes a repeating section of the ATXIN1 gene abnormally long. This repeated genetic code, “CAG,” is what encodes the amino acid glutamine in the resulting ataxin-1 protein. Therefore, in the cells of patients with SCA1, the Ataxin-1 protein is produced with an expanded string of glutamines, one after the other. This polyglutamine expansion makes the mutated ataxin-1 protein form clumps in many different types of cells – most notably, though, in the cells most affected in SCA1: the brain’s Purkinje cells.

Recent research suggests that these clumps, or “aggregates,” not only take up space in the cell, but that the act of ataxin-1 proteins clustering together might even be beneficial in early stages of disease (it’s possible that the proteins wreak less havoc when they’re in large clumps, rather than all floating around individually). However, another line of research suggests that ataxin-1 aggregates might also be toxic, triggering signals that lead to the cell’s death. As such, how exactly these aggregates affect the deterioration of cells has remained an important question in SCA1 research.

n a search for answers, an international team led by Stamatia Laidou designed a unique cell model of SCA1 to track the development of ataxin-1 aggregates. Their study, published in a recent paper, made use of normal human mesenchymal stem cells that had been engineered to make a modified version of the ataxin-1 protein. In these cells, ataxin-1 was produced not only with the SCA1-causing expansion, but also with a marker protein attached to its end. This marker, known as “green fluorescent protein” (GFP), is used extensively in biological research because it glows under fluorescent light.

doughnut with white and pink sprinkles
Laidou and colleagues have observed mutated ataxin-1 clumps that cause cell stress. Photo by Tim Gouw on Pexels.com

Using this to their advantage, Laidou and her team used a fluorescent microscope to follow the formation of ataxin-1 aggregates over the course of 10 days. The abnormal protein first started accumulating in the nucleus as small dots. As time went on, these dots started blending together, increasing in size. By ten days, the ataxin-1 aggregates had grown even more, forming a doughnut-shaped structure that occupied most of the cell’s nucleus – a crucial structure that houses the cell’s genetic information. These results were intriguing, since the accumulation of normal, non-expanded Ataxin-1 protein does not result in an aggregate with a doughnut shape.

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Spotlight: The Watt Lab

Watt lab logo of a neuron

Principal Investigator: Dr. Alanna Watt

Location: McGill University, Montreal, Canada

Year Founded: 2011

What disease areas do you research?

What models and techniques do you use?

Research Focus

What is your research about?

We are interested in how the cerebellum influences motor coordination in both the healthy brain and in models of disease and aging. By identifying changes in the cerebellum underlying ataxias and aging, we hope to discover new treatments for patients.

Why do you do this research?

We want to understand how the cerebellum works and use this knowledge to understand the changes in the cerebellum that lead to ataxia. As a lab, we are particularly interested in studying rare disorders like SCA6 and ARSACS.

These disorders have limited treatment options. We hope that by understanding how the cerebellum works differently in these disorders, we will be able to identify new treatments to help ataxia patients.

We are also interested in identifying common changes between different types of ataxia, to find out whether treatments identified in one form of ataxia might also help other ataxia patients.

Six slippers with a variety of designs, includes brain cells and mice

Fun Lab Fact

We got together and made our own slippers to keep cozy in our office. If you look at the picture closely you might be able to spot some cells from the cerebellum on some of them!

Image courtesy of Anna Cook.

For More Information, check out the Watt Lab Website!


Written by The Watt Lab, Edited by Celeste Suart

A New Use for Old Drugs

Written by Dr. Amy Smith-Dijak Edited by Logan Morrison

Basic biology helps identify a new treatment for ataxia

Drug design doesn’t always have to start with a blank slate. Sometimes understanding how existing drugs work can help researchers to design new ones, or even to recombine old drugs in new and more effective ways. That’s what the researchers behind this paper did. They investigated the basic biology of three existing drugs: chlorzoxazone, baclofen, and SKA-31.

Two of these – chlorzoxazone and baclofen – are already FDA-approved for use as muscle relaxants, and chlorzoxazone had previously been found to have a positive effect on eye movements in spinocerebellar ataxia type 6. Looking at the results of their experiments, they realized that a combination of chlorzoxazone and baclofen would probably be an effective treatment for ataxia over a long period. They offered this drug combination to patients, who had few adverse effects and showed improvement in their diseasesymptoms. Based on these findings, the researchers recommended that larger trials of this drug combination should be conducted and that people trying to design new drugs to treat ataxia should try to interact with the same targets as chlorzoxazone.

mutliple types of drugs in pill form scattered ac
Can old drugs have potential for new types of treatment? Photo by Anna Shvets on Pexels.com.

When this paper’s authors started their research, they wanted to know more about how ataxia changes the way that brain cells communicate with each other. Brain cells do this using a code made up of pulses of electricity. They create these pulses by controlling the movement of electrically charged atoms known as ions. The main ions that brain cells use are potassium, sodium, calcium and chloride. Cells control their movement through proteins on their surface called ion channels which allow specific types of ions to travel into or out of the cell at specific times. Different types of cells use different combinations of ion channels, which causes different types of ions to move into and out of the cell more or less easily and under different conditions. This affects how these cells communicate with each other.

For example, a cell’s “excitability” is a measure of how easy it is for that cell to send out electrical pulses. Creating these pulses depends on the right ions entering and exiting the cell at the right time in order to create one of these pulses. Multiple types of spinocerebellar ataxia seem to make it difficult for Purkinje cells, which send information out of the cerebellum, to properly control the pattern of electrical signals that they send out. This would interfere with the cerebellum’s ability to communicate with the rest of the brain. The cerebellum plays an important roll in balance, posture and general motor coordination, so miscommunication between it and the rest of the brain would account for many of the symptoms of spinocerebellar ataxias.

Earlier research had found a link between this disrupted communication and a decrease in the amount of some types of ion channels that let potassium ions into Purkinje cells. Thus, this paper’s authors wanted to see if drugs that made the remaining potassium channels work better would improve Purkinje cell communication.

Continue reading “A New Use for Old Drugs”

Snapshot: What is an action potential?

You may have heard that nerve cells (or neurons) in the brain use electrical activity to communicate with one another. The proteins responsible for creating these electrical signals are called ion channels. How do neurons use these electrical signals to communicate with one another in a meaningful way?

A good way to think about the brain is that it is wired into circuits. These brain circuits are not unlike the electrical circuits that power our home, computers, and cell phones. This means that within these circuits, an individual neuron must be able to send and receive electrical signals to and from its neighbors. The electrical signals used to transmit information down the length of a neuron are called action potentials.

cartoon of blue neurons sening small electrical signals to eachother
An artist’s drawing of action potentials (white) being sent out by neurons (blue) to communicate with eachother. Image courtesy of Flickr.

Brain communication: the action potential

Neurons use the electricity harnessed from the opening of ion channels to generate an action potential. Normally, when a neuron is not active, it rests at a negative resting state (or, a hyperpolarized membrane potential). This means that ion channels are closed and the neuron is not actively sending any signals to other neurons. Don’t worry, these voltages aren’t large enough to zap you! Neurons operate in a range between -90 millivolts and +40 millivolts, which is thousands of times smaller than the voltages that power circuits in our homes!

A neuron can become activated with the opening of certain ion channels, particularly ones that allow sodium ions into the neuron. Each time a sodium ion flows into the neuron, the membrane potential becomes slightly more positively charged, or depolarized. Once a specific threshold of depolarization is reached, a huge number of sodium channels open all at once and the cell’s membrane potential moves up to +20 mV.

Interestingly, another major type of ion channel, called a potassium channel, becomes activated on a slight delay compared to when sodium channels open. When potassium channels open, a large amount of positively-charged potassium quickly exits the neuron. This exit of potassium causes the membrane potential returns to its negative resting state. This allows the membrane to become hyperpolarized back to where it began. Now the cycle can start all over when another signal tells the neuron it is time to act. This whole cycle, from -70 mV to +20mV and back again, is the definition of an action potential. Action potentials quickly travel down the neuron in a single direction. Once they reach the end, they help generate a different type of chemical signal that tells the next neuron to generate an action potential of its own. And thus, the information continues to travel through the circuit.

An action potential is an all-or-none response. This means that if the threshold voltage is not reached, the neuron will remain silent and no action potential will be fired. In most neurons, a signal from a neighboring neuron causes the opening of sodium channels to help this signal initiate. However, in certain cell types (such as Purkinje neurons), action potentials can happen spontaneously, and all the time – sometimes even hundreds of times per second!

Approximate plot of a typical action potential shows its various phases as the action potential passes a point on a cell membrane. The membrane potential starts out at approximately −70 mV at time zero. A stimulus is applied at time = 1 ms, which raises the membrane potential above −55 mV (the threshold potential). After the stimulus is applied, the membrane potential rapidly rises to a peak potential of +40 mV at time = 2 ms. Just as quickly, the potential then drops and overshoots to −90 mV at time = 3 ms, and finally the resting potential of −70 mV is reestablished at time = 5 ms.
A diagram of how researchers plot a typical action potential. Image courtesy of WikiMedia.

Why do neuronal action potentials matter for cerebellar ataxia?

Researchers who study mouse models of ataxia have noticed that Purkinje neuron action potentials can undergo big changes during disease. Depending on the type of cerebellar ataxia, Purkinje neuron action potentials may take on a different shape or even disappear completely. Either of these situations could make it difficult, or even impossible, for a neuron to send proper signals to its neighbors. Some researchers suggest that improving action potential firing might be one way to improve ataxia symptoms. For this reason, identifying drugs that improve action potential firing is a major area of therapeutic research in ataxia.

If you would like to learn more about action potential, take a look at these resources by Khan Academy and Wikipedia.

Key Definitions

Membrane potential: the electrical voltage of a cell’s outer membrane. Changes in membrane potential are controlled by the opening and closing of many different types of ion channels.

Hyperpolarized: a negatively-charged membrane potential. A neuron usually rests at -70 mV when it is silent. It returns to that voltage after an action potential is completed.

Depolarized: a positively-charged membrane potential. This usually occurs when sodium channels open during the early part of an action potential. This cuases the cell quickly jumps up to +20 mV.

Snapshot written by David Bushart and edited by Celeste Suart.

Finding New Off-Balance Protein Networks in SCA7

Written by Frida Niss Edited by Dr. Siddharth Nath

Can neurodegeneration in SCA7 in part be due to faulty calcium homeostasis in the cerebellum?

Polyglutamine diseases are caused by an increase in the length of CAG repeats within a specific gene. The mutation for spinocerebellar ataxia type 7 (SCA7) was discovered more than two decades ago, but many of the details surrounding how the mutation actually causes disease remain fuzzy. We know that the increased repeat length in the gene makes it difficult for the resulting protein to arrange or fold itself properly. We also know that the mutated protein binds to itself and to other proteins in an unusual way. It building up large deposits of seemingly useless debris in the cell, called ‘aggregates’. However, the exact pathways this leads to cell death, and subsequently neurodegeneration, is not completely clear.

There is currently research underway to directly target and inhibit the repeat proteins themselves. However, finding other pathways in the cell that are easier to target with medication is also a priority. In this research, Stoyas and her colleagues wanted to find out more about which cellular pathways are disturbed in the polyglutamine disease SCA7.

A pair of hands in plastics gloves writes down scientific findings on a chart. Beside the hands are racks of tubes with lables of different samples and dates collected.
A laboratory scientist documents research findings. Image courtesy of the National Institutes of Health on Flickr.
SCA7 mice have disordered productions of proteins that help balance ions concentrations

In SCA7, the protein that carries the mutation is Ataxin-7. Ataxin-7 participates in transcription through complexes of proteins that together can change some signalling particles on the DNA. Depending on what signalling particles are attached to a certain gene, the gene is either transcribed and made into a protein, or “silenced” and skipped over. In the case of Ataxin-7 and its complex, they work together to cause transcription of genes. One of the main theories of how a polyglutamine mutation can be toxic in Ataxin-7 is that the mutation disturbs Ataxin-7’s normal function within this transcription activating complex. Instead of being regular and orderly, ataxin-7 starts acting unpredictably. Some things that should be transcribed are not, some that shouldn’t be transcribed are.

Continue reading “Finding New Off-Balance Protein Networks in SCA7”