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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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.

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The importance of balancing Sacsin protein levels in ARSACS

Written by Dr. Ambika Tewari Edited by Larissa Nitschke

Tipping the balance of the protein Sacsin alters outcomes in a mouse model of ARSACS

There are many different types of ataxia, each with a unique cause. For several ataxias, the mutated gene that causes the disorder has been identified. This is a great achievement that we owe to recent advancements in genome sequencing. Knowing the gene that is altered in a disorder provides researchers with a solid foundation to understand the mechanisms underlying the disease. In the neurodegenerative disorder Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), this alteration occurs in the SACS gene. Currently, over 170 different SACS gene mutations have been identified in human patients. Because each gene is equipped with a specific set of instructions to make a protein, each mutation can cause a change in these instructions. This usually results in the production of very little sacsin protein – or no protein at all. In several disorders, it has been shown that maintaining optimal levels of a variety of proteins is crucial to the proper functioning of the nervous system.

In 2015, a group of researchers wanted to understand why the loss of the protein sacsin produced certain symptoms in ARSACS patients. To study this, they removed the entire SACS gene from a mouse (known as the Sacs-/-  line), which meant that these mice made no sacsin protein. Mice with only one copy of this mutation (Sacs+/-) could produce up to 50% of the protein. In this same study, the researchers also wanted to make a more disease-relevant mouse model, so they made a mouse with a mutation known as “R272C.” R272C was a SACS gene mutation that was initially identified in a patient with ARSACS. Mice with two copies of the mutated gene (SacsR262C/R262C) had sacsin levels reduced to 21%, whereas mice with one copy (SacsR262C/+) had 65% of sacsin levels. Together, these mouse models provided the researchers with a group of mice that had a range of sacsin protein levels. These mice could then be used to understand how changes in the levels of sacsin affect behavior, especially in the ways that we might observe in ARSACS.

brown laboratory mouse being held by rsearcher with blue gloved hands
Stock image of a laboratory research mouse, similar to the R272C ARSACS mouse. Image courtesy of Rama on Wikimedia Commons.

ARSACS patients have a childhood onset of ataxia that worsens over time. This is due to the loss of Purkinje cells in the cerebellum, the area of the brain that controls motor coordination. Without Purkinje cells, the cerebellum cannot properly function, resulting in the uncoordinated gait that we call “ataxia.” The researchers found that mice with less than 50% sacsin protein also displayed progressive motor abnormalities (measured using three well-established mouse coordination tests). These mice also showed degeneration of Purkinje cells, which became more apparent with increasing age. Moreover, as protein levels decreased, motor performance and Purkinje cell loss became more pronounced.

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Concevoir une stratégie thérapeutique unique pour traiter plusieurs types d’ataxie spinocérébelleuse

Écrit par Dr David Bushart, Édité par Dr Hayley McLoughlin, Traduction française par: L’Association Alatax, Publication initiale: 3 janvier 2020

Une stratégie de traitement nouvellement proposée pourrait être efficace contre plusieurs formes d’ataxie spinocérébelleuse et d’autres troubles associés aux répétitions CAG.

Lors de la réception d’un diagnostic initial d’ataxie spinocérébelleuse (SCA), un essaim de questions peut pénétrer dans l’esprit du patient. Bon nombre de ces questions porteront probablement sur la façon de gérer et de traiter leur maladie. Quels traitements sont actuellement disponibles pour traiter la SCA? Que puis-je faire pour réduire les symptômes? Le SCA a-t-il un remède, et sinon, les chercheurs sont-ils sur le point d’en trouver un ?

Les patients et les membres de la famille qui lisent SCASource peuvent être en mesure de répondre à certaines de ces questions.

Bien que les scientifiques soient conscients de certaines des causes génétiques sous-jacentes de la SCA et que les patients puissent grandement bénéficier de l’exercice et de la physiothérapie, il n’existe malheureusement aucune thérapie médicamenteuse actuelle qui puisse traiter efficacement ces maladies.

Cependant, c’est une période très excitante dans la recherche sur les SCA, car les chercheurs travaillent dur pour développer de nouvelles stratégies de traitement pour plusieurs des SCA les plus courants. Beaucoup de ces thérapies nouvellement proposées sont spécialisées pour traiter un sous-type génétique spécifique de SCA (par exemple SCA1, SCA3, etc.), ce qui permettrait à ces thérapies d’être très spécifiques. Cependant, ces efforts spécialisés soulèvent une autre question : serait-il possible de traiter différents types de SCA avec la même stratégie thérapeutique ?

sketch of a human brain and spinal cord across a blue background
Croquis de l’artiste d’un cerveau humain. Image reproduite avec l’aimable autorisation de Pixabay.

C’est précisément ce que les chercheurs ont voulu déterminer dans une étude récente, rédigée par Eleni Kourkouta et ses collègues. Ce groupe de chercheurs a utilisé une technologie appelée oligonucléotides antisens (souvent en abrégé ASO, ou AON), pour se demander si un seul ASO pourrait être utilisé pour traiter plusieurs troubles neurologiques qui ont différentes causes sous-jacentes. Actuellement, la plupart des technologies ASO dépendent de notre capacité à cibler sélectivement des gènes spécifiques causant des maladies, ce qui permet à l’ASO de reconnaître et d’agir uniquement sur le gène spécifique qui cause l’ataxie. Une fois reconnus, ces ASO peuvent recruter des machines cellulaires qui abaissent les niveaux d’ARN du gène pathogène, limitant ainsi considérablement la quantité de protéines pathogènes produites (en savoir plus dans notre aperçu de l’ARN, qu’est-ce que l’ARN?). Cette stratégie a le potentiel d’être très efficace pour traiter les SCA associés à l’expansion de la polyglutamine (polyQ).

Cependant, le type de technologie ASO décrit ci-dessus n’est pas le seul moyen de réduire les niveaux des protéines pathogènes dans SCA. Dans cet article, Kourkouta et ses collègues utilisent un type différent d’ASO avec un mécanisme d’action différent, ce qui réduit également les niveaux de la protéine pathogène dans deux SCA différents.

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Two or more birds with one stone: Designing a single therapeutic strategy to treat multiple types of spinocerebellar ataxia

Written by Dr. David Bushart Edited by Dr. Hayley McLoughlin

A newly-proposed treatment strategy might be effective against several forms of spinocerebellar ataxia and other CAG repeat-associated disorders

Upon receiving an initial diagnosis of spinocerebellar ataxia (SCA), a swarm of questions might enter a patient’s mind. Many of these questions will likely revolve around how to manage and treat their disease. What treatments are currently available to treat SCA? What can I do to reduce symptoms? Does SCA have a cure, and if not, are researchers close to finding one? Patients and family members who read SCASource may be able to answer some of these questions. Although scientists are aware of some of the underlying genetic causes of SCA, and patients can benefit greatly from exercise and physical therapy, there are unfortunately no current drug therapies that can effectively treat these diseases. However, this is a very exciting time in SCA research, since researchers are hard at work developing new treatment strategies for several of the most common SCAs. Many of these newly proposed therapies are specialized to treat a specific genetic subtype of SCA (e.g. SCA1, SCA3, etc.), which would allow these therapies to be very specific. However, these specialized efforts beg another question: would it be possible to treat different types of SCA with the same therapeutic strategy?

sketch of a human brain and spinal cord across a blue background
Artist’s sketch of a human brain. Image courtesy of Pixabay.

This is precisely what researchers wished to determine in a recent study, authored by Eleni Kourkouta and colleagues. This group of researchers used a technology called antisense oligonucleotides (often abbreviated ASO, or AON), to ask whether a single ASO could be used to treat multiple neurological disorders that have different underlying causes. Currently, most ASO technology depends on our ability to selectively target specific disease-causing genes, which allows the ASO to only recognize and act on the specific gene that is causing ataxia. Once recognized, these ASOs can recruit cellular machinery that lowers RNA levels of the disease-causing gene, thereby greatly limiting the amount of disease-causing protein that is produced (learn more in our What is RNA? Snapshot). This strategy has the potential to be very effective for treating SCAs that are associated with polyglutamine (polyQ) expansion (learn more in our What is Gene Therapy? Snapshot).

However, the type of ASO technology described above is not the only way to reduce levels of the disease-causing proteins in SCA. In this paper, Kourkouta and colleagues use a different type of ASO with a different mechanism of action, which also lowers levels of the disease-causing protein in two different SCAs.

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