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.

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

Spotlight: The Neuro-D lab Leiden

Principal Investigator: Dr. Willeke van Roon-Mom

Location: Leiden University Medical Centre, Leiden, The Netherlands

Year Founded: 1995

What disease areas do you research?

What models and techniques do you use?

A group photo of members of the Neuro-D lab Leiden standing outside on a patio.
This is a group picture taken during our brainstorm day last June. From left to right: Boyd Kenkhuis, Elena Daoutsali, Tom Metz, Ronald Buijsen, Willeke van Roon-Mom (PI), David Parfitt, Hannah Bakels, Barry Pepers, Linda van der Graaf and Elsa Kuijper. Image courtesy of Ronald Buijsen.

Research Focus

What is your research about?

The Neuro-D research group studies how diseases develop and progress at the molecular level in several neurodegenerative diseases. They focus on diseases that have protein aggregation, where the disease proteins clump up into bundles in the brain and don’t work correctly.

We focus strongly on translational research, meaning we try to bridge the gap between research happening in the laboratory to what is happening in medical clinics. To do this we use more “traditional” research models like animal and cell models. But we also use donated patient tissues and induced pluripotent stem cell (iPSC) models, which is closer to what is seen in medical clinics.

Our aim is to unravel what is going wrong in these diseases, then discover and test potential novel drug targets and therapies.

One thing we are doing to work towards this goal is identifying biomarkers to measure how diseases progress over time. To do this, we use sequencing technology and other techniques to look at new and past data from patients.

Why do you do this research?

So far there are no therapies to stop the progression of ataxia. If we can understand what is happening in diseases in individual cells, we can develop therapies that can halt or maybe even reverse disease progression.

Identifying biomarkers is also important, because it will help us figure out the best time to treat patients when we eventually have a therapy to test.

Stylized logo for the Dutch Center for RNA Therapeutics
The Neuro-D lab Leiden is part of the Dutch Center for RNA Therapeutics, which focuses on RNA therapies like antisense oligonucleotides. Logo designed by Justus Kuijer (VormMorgen), as 29 year old patient with Duchenne muscular dystrophy.

Are you recruiting human participants for research?

Yes, we are! We are looking for participants for a SCA1 natural history study and biomarker study. More information can be found here. Please note that information about this study is only available in Dutch.

Fun Fact

All our fridges and freezers have funny names like walrus, seal, snow grouse and snowflake.

For More Information, check out the Neuro-D lab Leiden website!


Written by Dr. Ronald Buijsen, Edited by Celeste Suart

Spotlight: The Truant Lab

Truant lab logo of a brain. "Bright minds fixing sick brains"

Principal Investigator: Dr. Ray Truant

Location: McMaster University, Hamilton, Ontario, Canada

Year Founded: 1999

What disease areas do you research?

  • SCA1
  • SCA7
  • Huntington’s Disease
  • Parkinson’s Disease

What models and techniques do you use?

  • Human cell biology
  • High content screening
  • Biophotonics
  • Microscopy

Research Focus

What is your research about?

We are looking into the role of oxidative DNA damage as a trigger to diseases like ataxia and neurodegeneration. We examine the roles of the disease proteins (ataxin-1, ataxin-7, etc,) and genes which modify or change disease that are involved with DNA damage repair.

Why do you do this research?

We are looking at what triggers the very first steps of disease. If we can understand this, we can design a treatment to stop it from happening in the first place.

Research team of 10 holding a sign which reads "We are Ataxia Aware"
Group picture of the Truant Laboratory celebrating International Ataxia Awareness Day 2019.

Fun Lab Fact

All our fridges in the laboratory are named after Game of Thrones characters! (We have several proud nerds in the lab)

For More Information, check out the Truant Lab Website!

We have an open lab notebook blog where our post-doctoral fellow Dr. Tam Maiuri post updates on her experiments in real-time! We plan to launch an ataxia open notebook in Winter 2021.


Written by Ray Truant, 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”

The Cognitive Deficits of Mice and Men: How the cerebellum contributes to the cognitive symptoms of SCA1

Written by Kim M. Gruver Edited by David Bushart

What’s cognition got to do with ataxia? Could the cerebellum mediate both cognitive and motor symptoms in the same disease? And how can scientists use mice to find out?

Spinocerebellar ataxia type 1, or SCA1, is a progressive neurodegenerative disease that has no cure. In SCA1, an expanded CAG repeat sequence in the ATXN1 gene increases the chain length of the amino acid glutamine (Q), so SCA1 is called a “polyQ” disease. As suggested by its name, the cerebellum is a heavily affected brain region in SCA1. Since the cerebellum is involved in motor coordination, it is no surprise that dysregulated control of movement, or ataxia, is a major symptom of SCA1.

However, what may come as a surprise is that some SCA1 patients also experience changes in cognition in addition to ataxia. Since the mutated ATXN1 gene is found throughout the brain, it has been difficult to tease apart whether the cerebellum contributes to the cognitive symptoms of SCA1 in addition to the motor symptoms. It is possible that cognitive symptoms of SCA1 might be exclusively caused by brain regions other than the cerebellum. For example, ATXN1 is also highly expressed in the prefrontal cortex, a region known for mediating many cognitive processes. But before we discount the possibility that the cerebellum plays a role in the cognitive symptoms experienced by some SCA1 patients, it is important to note an interesting observation in neuroscience research that has emerged in recent decades. Scientists have described a surprising role of the cerebellum in a host of neurological disorders like autism and schizophrenia. In light of these findings, that the cerebellum could be implicated in both the motor and cognitive symptoms of SCA1 may not be so far-fetched.

two borwn lab mice held in the hand of a researcher wearing plastic gloves
Two lab mice from the National Institutes of Health, image courtesy of WikiMedia.

A powerful tool on the researcher’s lab bench to study diseases like SCA1 is the laboratory mouse. Since 1902, mice have played an indispensable role in disease research. Scientists can breed mice that express human genes, such as a mutated form of ATXN1, to figure out what goes awry in diseases like SCA1. Animal models of disease help researchers to identify potential treatment strategies that may be useful to humans. Since such in-depth analysis and careful experimental manipulation is impossible in human patients, animal models are an invaluable tool to study diseases like SCA1.

In the SCA1 field, scientists use multiple animal models to study SCA1. Researchers have harnessed the differences between these mouse models to address different questions, such as:

  • “How does the number of CAG repeats affect SCA1 symptoms in mice?”
  • “What happens if the ATXN1 gene is removed altogether?”
  • “Do SCA1 symptoms still occur if the mutant ATXN1 gene is restricted to cerebellar Purkinje cells?

 In mice and in humans, we know that the length of the polyQ expansion in the ATXN1 gene correlates with both the severity and the age of symptom onset of SCA1. Mice that express more CAG repeats (a longer polyQ expansion) in their ATXN1 gene experience more severe symptoms that start earlier in life than mice with a shorter polyQ expansion. When mutant ATXN1 expression is restricted to Purkinje cells in the cerebellum, mice display motor impairments similar to what is observed in mice with mutant ATXN1 expression everywhere in the brain. This tells us that disrupting healthy ATXN1 expression in Purkinje cells alone is sufficient to cause motor symptoms that stem from SCA1. To put it plainly, mouse models of SCA1 have been a crucial component of SCA1 research.

Since human SCA1 patients experience behavioral symptoms, scientists also use behavioral tools to evaluate the symptoms of SCA1 mice. Motor coordination tests are essential in ataxia research. These tests allow scientists to determine whether a potential intervention improves or worsens symptoms in mice. This is the first step to evaluate whether an intervention could be promising for human patients. However, as we discussed earlier, motor impairments are not the only symptom faced by SCA1 patients: many exhibit cognitive deficits as well. But could mice be used to evaluate something as complex as cognition? Can laboratory mice really help scientists uncover whether the cerebellum contributes to the cognitive impairments observed in SCA1? Researchers at the University of Minnesota say yes.

Continue reading “The Cognitive Deficits of Mice and Men: How the cerebellum contributes to the cognitive symptoms of SCA1”