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.

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Snapshot: What is Omaveloxolone?

A new therapeutic compound shows promise to treat Friedrich’s ataxia.

What is Friedrich’s ataxia (FA)?

Friedrich’s ataxia is a genetic neurodegenerative disease that affects many organs, most notably nerves, muscles, and heart. FA is a recessive ataxia. Symptoms typically present in childhood and result in significant physical disability. Cognition (thinking, memory) remains intact.

Some of the symptoms a person with FA may experience include ataxia (loss of movement coordination), fatigue, muscle weakness, cardiomyopathy (heart issues), scoliosis (curvature of the spine) and sensory impairments (vision, hearing). Life expectancy is reduced as a result of the disease.

The genetic change that is present in FA affects the production of a protein called frataxin. Frataxin deficiency leads to abnormal iron accumulation in mitochondria.  As mitochondria are critical for energy metabolism and other important functions in cells, their dysfunction causes faulty energy production and undesirable toxicity in the form of reactive oxygen species.

There is currently no treatment available to patients with FA.

white medical pills in the shape of a question mark
What is Omaveloxolone? How could it help people with Friedrich’s Ataxia? Photo by Anna Shvets on

How does Omaveloxolone work?

Omevaloxolone is a synthetic compound. It works by counteracting deficits seen in disease at the cellular level. Omevaloxolone promotes Nrf2, which works to activate a series of defence mechanisms that help cells handle oxidative stress (mentioned above). Nrf2 is also important for improving the energy production machinery mitochondria require to function efficiently. Thus, by activating Nrf2, Omevaloxolone is thought to mitigate oxidative damage, improve energy production, and promote neuroprotection. Additionally, Omevaloxolone and similar compounds exhibit anti-inflammatory action.

What exactly has been validated?

In the MOXIe clinical trial, study participants with FA from several countries were randomized to either daily omaveloxolone (drug) or placebo (control). Their neurological function, activities of daily living, and ataxia were assessed at baseline (at the beginning) and after 48 months of receiving treatment. At the end of this period, the data showed statistically significant improvement in each of these measures. Participants who received omaveloxolone fared better than those who did not (placebo). Additionally, participants who received omaveloxolone saw improvements after treatment compared to their own baseline at the beginning of the study.

What is happening next?

The next step in testing omaveloxolone is to have a long-term study to examine its safety (and any side effects) over the course of a few years. Instead of having a control group in this type of study, called an open-label extension, now everyone enrolled received the same amount of omaveloxolone. This study is already underway and is expected to be completed by 2022. There have been some modifications to the long-term safety study in response to COVID-19, but Reata doesn’t expect there to be a significant delay in their timelines.

If you would like to learn more about omaveloxolone, take a look at these resources by the Reata Pharmaceuticals and To learn more about Friedrich’s Ataxia, visit the Friedrich’s Ataxia Research Alliance website.

Snapshot written by Dr. Judit M. Pérez Ortiz and edited by Larissa Nitschke.

New molecule can reverse the Huntington’s disease mutation in lab models

Written by Dr. Michael Flower Edited by Dr. Rachel Harding

Editor’s Note: This article was initially published by HDBuzz on March 13, 2020. They have graciously allowed us to build on their work and add a section on how this research may be relevant to ataxia. This additional writing was done by Celeste Suart and edited by David Bushart.

A collaborative team of scientists from Canada and Japan have identified a small molecule which can change the CAG-repeat length in different lab models of Huntington’s disease.

CAG repeats are unstable

Huntington’s disease is caused by a stretch of C, A and G chemical letters in the Huntingtin gene, which are repeated over and over again until the number of repeats passes a critical limit; at least 36 CAG-repeats are needed to result in HD.

In fact, these repeats can be unstable, and carry on getting bigger throughout HD patients’ lives, but the rate of change of the repeat varies in different tissues of the body.

In the blood, the CAG repeat is quite stable, so an HD genetic blood test result remains reliable. But the CAG repeat can expand particularly fast in some deep structures of the brain that are involved in movement, where they can grow to over 1000 CAG repeats. Scientists think that there could be a correlation between repeat expansion and brain cell degeneration, which might explain why certain brain structures are more vulnerable in HD.

a print out of genetic information show as a list of A,T, C, and G letters
The CAG repeat of the huntingtin gene sequence can be changed to include more and more repeats, in a process called repeat expansion. This can also happens in some ataxia related genes. Image credit: “Gattaca?” by IRGlover is licensed under CC BY-NC 2.0

But why?

This raises the question, what is it that’s causing the CAG repeat to get bigger? It seems to be something to do with DNA repair.

We’re all exposed continually to an onslaught of DNA damage every day, from sunlight and passive smoking, to ageing and what we eat. Over millions of years, we’ve evolved a complex web of DNA repair systems to rapidly repair damage done to our genomes before it can kill our cells or cause cancer. Like all cellular machines, that DNA repair machinery is made by following instructions in certain genes. In effect, our DNA contains the instructions for repairing itself, which is quite trippy but also fairly cool.

What is it that’s causing the CAG repeat to get bigger? 

We’ve known for several years that certain mouse models of HD have less efficient systems to repair their DNA, and those mice have more stable CAG repeats. What’s more, deleting certain DNA repair genes altogether can prevent repeat expansion entirely.

But hang on, isn’t our DNA repair system meant to protect against mutations like these?? Well normally, yes. However, it appears a specific DNA repair system, called mismatch repair, sees the CAG repeat in the huntingtin gene as an error, and tries to repair it, but does a shoddy job and introduces extra repeats.

Why does this matter?

There’s been an explosion of interest in this field recently, largely because huge genetic studies in HD patients have found that several DNA repair genes can affect the age HD symptoms start and the speed at which they progress. One hypothesis to explain these findings is that slowing down repeat expansion slows down the disease. What if we could make a drug that stops, or even reverses repeat expansion? Maybe we could slow down or even prevent HD.

Continue reading “New molecule can reverse the Huntington’s disease mutation in lab models”

Snapshot: What does dominant ataxia mean?

Ataxias can occur due to a multitude of reasons. One way a patient might acquire ataxia is from an accident or an injury – not as a result of genetics. On the other hand, a patient could also inherit a specific mutation (a genetic defect, in other words) from one or both of their parents. In this case, the ataxia is called “hereditary.” Hereditary ataxias can be further classified as either “dominant” or “recessive.”

What is a dominantly-inherited disorder?

Most genes in our body have two copies: one that we inherit from our mother, and one that we inherit from our father. Dominantly-inherited disorders are diseases in which a mutation in just one copy of a gene is enough to cause disease. When both copies of a gene need to be mutated to cause symptoms, the disorder is known as “recessive” (learn more in the Snapshot on recessive ataxias). For a patient with a dominantly-inherited ataxia, this means that there is a 1-in-2 chance that their children will inherit the disease-causing mutation (assuming that their spouse is unaffected). If both spouses are affected by the same dominantly-inherited disease, this chance increases to 3-in-4. In cases where the child inherits both mutant copies of the gene, the symptoms are often more severe than when a single copy is inherited.

Visual depiction of paragraph above
How dominant disorders are inherited. Illustration by Larissa Nitschke, created with BioRender.

Which ataxias are dominantly-inherited?

The most well-known ataxias with dominant inheritance patterns are the Spinocerebellar Ataxias (SCAs), such as SCA1, SCA2, SCA3, SCA6, and SCA7. Each disease is caused by defects in a different gene. Due to the high similarity in symptoms among all ataxias, genetic testing is often required to determine the exact gene mutation and type of ataxia a patient has.

How can a patient prevent passing on a dominantly-inherited disorder to their children?

There are multiple options to prevent passing on the disease to your child if you are affected by a hereditary ataxia. One potential option is to perform in vitro fertilization (IVF), a technology that is used the conceive embryos outside the human body. The embryos can be screened for genetic mutations, allowing only the healthy embryos to be implanted into the uterus.

If you are affected by a hereditary ataxia and want to prevent having a child with ataxia, it is recommended to talk to your physician and genetic counselor regarding reproductive options.

If you would like to learn more about in vitro fertilization and embryo screening, please take a look at these resources by the University of Pennsylvania. If you want to learn more about dominant ataxia, take a look at these resources by the National Organization for Rare Disorders and Ataxia Canada.

Snapshot written by Larissa Nitschke and edited by Dr. Marija Cvetanovic.

Byproducts of canola oil production show therapeutic potential for MJD and Parkinson’s Disease

Written by Dr. Maria do Carmo Costa, Edited by Dr. Hayley McLoughlin

Collaboration between researchers in Portugal and the United Kingdom discover that a canola oil by-product shows promise, corrects MJD/SCA3 and Parkinson’s Disease symptoms in animal models.

Isolated compounds or extracts (containing a mixture of compounds) from certain plants are showing promise as potential anti-aging drugs or as therapeutics for neurodegenerative diseases. Some of these plant compounds or extracts can improve the capacity of cells to fight oxidative stress that is defective in aging and in some neurodegenerative diseases. Machado-Joseph disease, also known as Spinocerebellar ataxia type 3, and Parkinson’s disease are two neurodegenerative diseases in which cells inability to defend against oxidative stress contributes to neuronal death. In this study, the groups of Dr. Thoo Lin and Dr. Maciel partnered to test the therapeutic potential of an extract from the canola plant rapeseed pomace (RSP) with antioxidant properties in Machado-Joseph disease and Parkinson’s disease worm (Caenorhabditis elegans) models.

Canola field with snowcapped mountains in the background, July 1990
Canola field with snowcapped mountains in the background, image courtesy of USDA NRCS Montana on Flickr.

Machado-Joseph disease is a dominant neurodegenerative ataxia caused by an expansion of CAG nucleotides in the ATXN3 gene resulting in a mutant protein (ATXN3). While in unaffected individuals this CAG repeat harbors 12 to 51 trinucleotides, in patients with Machado-Joseph disease contains 55 to 88 CAG repeats. As each CAG trinucleotide in the ATXN3 gene encodes one amino acid glutamine (Q), the disease protein harbors a stretch of continuous Qs, also known as polyglutamine (polyQ) tract.

Parkinson’s disease that is characterized by loss of dopaminergic neurons can be caused either by genetic mutations or by environmental factors. Mutations in the genes encoding the protein a-synuclein and the enzyme tyrosine hydroxylase (a crucial enzyme for the production of dopamine) are amongst the genetic causes of patients with Parkinson’s disease.

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