Clearing aggregated ataxin-2 protein as a therapeutic avenue for SCA2

Written by Dr. Vitaliy Bondar Edited by Dr. Hayley McLoughlin

New research suggests that mutant ataxin-2 protein overwhelms cells in SCA2, leading to decreased autophagy and clearance of damaged proteins.

Many comparisons can be made between cells and human beings. Just like humans, cells can accumulate junk and waste at certain times and this clutter overtime becomes problematic and even toxic. This is precisely what Jonathan Henry Wardman and colleagues from the University of Copenhagen decided to investigate on a cellular level. They asked whether the lack of appropriate clearance of faulty disease proteins effect cellular survival and wellbeing.

The researchers chose to study cells derived from a patient that has Spinocerebellar ataxia type 2 (SCA2). The cause of SCA2 is CAG repeat expansion in the ATAXIN-2 gene, which encodes polyglutamine amino acid chain in an RNA-binding protein, ataxin-2. The faulty polyQ expanded ATXN2 protein is found to aggregate inside the cell and overtime can affect its survival. Accumulation of aggregated protein products derived from mutated genes is a hallmark of many types of spinocerebellar ataxias as well as other forms of neurodegenerative disorders such as Parkinson’s disease.

It is unclear how protein aggregation impacts cellular survival. However, multiple cellular defects have been correlated with ataxin-2 aggregation. For instance, mitochondria which generates energy for a cell, has been reported to abnormally function in SCA2 cellular models. Additionally, a cellular clearance mechanism, called autophagy, which is responsible for clearing faulty cellular compartments and certain broken proteins is shown to be less effective in various SCA2 models. These mechanisms the authors decided to investigate in their recently published research article.

scientist using microscope
New research using SCA2 cells sheds light on what causes disease symptoms to occur. Photo by Chokniti Khongchum on

The scientists first identified evidence of SCA2 cellular dysfunction through detection of significant elevation of caspase-9 and caspase-8 levels. These are protein which indicate cellular stress and death. The authors hypothesized that such cellular dysfunction may arise from accumulation of faulty ataxin-2. In order to test this hypothesis, they decided to systematically block two cellular pathways that process defective proteins: proteostasis and autophagy.

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A new molecule identified that controls cerebellar communication

Written by Dr. Ambika Tewari Edited by Dr. Sriram Jayabal

Targeting phosphatases in the cerebellum can correct miscommunication in multiple models of ataxia.

The cerebellum is essential for motor coordination and consists of the coordinated activity of different types of cells. Purkinje cells are one of the most fascinating cell types in the cerebellum. They have an elaborate network of branches called dendrites, where a neuron receives communication from other neurons. It is one of the most complex branching systems seen across all neurons in the entire brain. Each one of these branches has many points of contact with other branches called axons. Each axon is part of a neuronal structure that allow communication between neurons. These axons are from different cell types and allow information to be transferred to Purkinje cells.

Colourful illustration of a human brain
Targeting phosphatases in the brain could improve communication between neurons, reducing ataxia symptoms.

Due to this branching complexity, Purkinje cells receive many messages or inputs. This represents different pieces of sensory information to ensure that movements are precisely timed. Purkinje cells must integrate and process this information. This produces motor behaviors like walking, writing, playing a musical instrument, and many more. Any alteration to the processing of this information will result in cerebellum dysfunction; in fact, Purkinje cells have gained attention because they undergo progressive deterioration in most ataxias. 

Neurons, including Purkinje cells, communicate with other neurons using electrical signals known as action potentials or spikes. Firing rate, defined as the number of spikes within a defined period of time, is thought to be an important feature of this communication, which is critical for coordinating muscle movements. Therefore, a lower firing rate in Purkinje cells would signal a faulty communication between Purkinje cells and their targets. This has devastating consequences as seen in many ataxias.

For instance, in an earlier study, a group of authors found that the firing rate of Purkinje cells was decreased in mouse models of three different Spinocerebellar ataxias (SCAs): SCA1, SCA2, and SCA5. They further explored whether there was a common reason underlying the decreased firing rate. They found that a protein named Missing in Metastasis (MTSS1), was important for Purkinje cells to effectively communicate with each other. Mice engineered to have no MTSS1 protein had a decreased firing rate and difficulty walking and maintaining their balance.

In every cell in the body, including brain cells, there are numerous proteins that perform different functions. The concerted effort of all are needed for the cell to perform its intended duty. Some of these proteins are maintained in the cell in an inactive form and are activated when they are required in the cell and inhibited when they are not. This highly regulated system aims to maintain precise levels of proteins in each cell, while simultaneously conserving energy. Each cell has many ways of activating/inactivating a protein. A specialized group of proteins known as kinases and phosphatases, adds and removes phosphate groups to and from proteins respectively, thereby altering their active/inactive forms which then changes their interactions with other proteins. MTSS1 is one such protein that inhibits the activity of a group of kinases known as Src family of non-receptor tyrosine kinases (SFKs).

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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

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.

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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.

Les yeux, des fenêtres pour voir la fonction cérébrale dans les ataxies spinocérébelleuses

Écrit par Dr Sriram Jayabal, Édité par Dr David Bushart, Traduction française par: L’Association Alatax, Publication initiale: 20 décembre 2019 

Les déficits de mouvement oculaire se produisent de manière omniprésente dans les ataxies spinocérébelleuses, même aux premiers stades de la maladie, soulignant leur importance clinique.

Imaginez les différents mouvements moteurs que vous effectuez dans votre vie quotidienne. Beaucoup de gens pensent aux actions que nous effectuons en utilisant nos mains et nos jambes, comme atteindre des objets ou marcher. Zoomons sur une autre tâche : attraper une balle de baseball. Vous devez savoir où la balle va atterrir pour pouvoir courir jusqu’à cet endroit, puis guider vos bras pendant la plongée, si nécessaire, pour attraper la balle. Pour que cela fonctionne parfaitement, vous devez voir et suivre la balle. Vos yeux vous permettent de suivre la balle pendant qu’elle se déplace. Comment vos yeux peuvent-ils garder le ballon au point pendant que vous courez à pleine vitesse vers l’endroit où vous vous attendez à ce que le ballon atterrisse ? Vos yeux sont équipés de muscles qui permettent aux yeux de bouger afin de garder la scène visuelle au point. Ces mouvements oculaires, comme l’exigent les besoins du scénario actuel, dans ce cas, attraper une balle de baseball, nous sont indispensables pour voir le monde sans aucune entrave.

Woman with hand in a "C" shape in front of her face. She's focusing in on her eye.
Les yeux peuvent fournir une fenêtre sur l’ataxie spinocérébelleuse, avant même que d’autres symptômes n’apparaissent. Photo de fotografierende sur

Quelle région du cerveau nous donne le pouvoir de le faire?

C’est le cervelet qui permet de bouger les bras et les jambes avec précision, contrôle également la façon dont nous bougeons nos yeux. Par conséquent, il est logique d’affirmer que lorsque le cervelet tourne mal, cela peut entraîner des anomalies des mouvements oculaires. Plusieurs études antérieures ont montré que cela était vrai dans de nombreuses ataxies spinocérébelleuses (SCA), où des symptômes non liés à la marche tels que des anomalies des mouvements oculaires se sont avérés accompagner les déficits de la marche aux stades avancés de la maladie. Cependant, des travaux récents de pionniers de la recherche clinique sur l’ataxie à la Harvard Medical School ont montré que les anomalies des mouvements oculaires sont également couramment présentes dans les SCA, même dans les états pré-symptomatiques. Cette étude met l’accent sur la nécessité cruciale de mieux documenter l’historique des déficits des mouvements oculaires et de les suivre tout au long de la progression de la maladie. Cela aidera les chercheurs à développer de meilleures échelles d’évaluation de l’ataxie.

Dans cette étude, une population de patients SCA (134 individus) qui présentaient différents types de SCA (y compris SCA1, SCA2, SCA3, SCA5, SCA6, SCA7, SCA8 et SCA17) ont été évalués pour les anomalies des mouvements oculaires à différents stades de la maladie, du stade pré-symptomatique (sans déficit de marche) au stade avancé (ceux qui utilisent un fauteuil roulant). Premièrement, il a été constaté que ~ 78% de tous les individus pré-symptomatiques présentaient des déficits de mouvement oculaire, et ces déficits sont devenus encore plus courants à mesure que la maladie progressait, où chaque personne à un stade avancé présentait des déficits de mouvement oculaire.

Deuxièmement, lorsque les chercheurs ont examiné de près les mouvements oculaires, ils ont constaté que différents types d’ataxie pouvaient provoquer différents types de déficits des mouvements oculaires.

Cependant, ces résultats ne sont que suggestifs en raison de la faible population d’individus SCA à un stade précoce dans cette étude et des types d’évaluations utilisées. Par conséquent, les études futures nécessiteront une plus grande taille de la population et une analyse quantitative approfondie des types spécifiques de déficits de mouvement oculaire pour aider à caractériser les anomalies du mouvement oculaire dans les SCA. Enfin, la Brief Ataxia Rating Scale (BARS), un test clinique simple récemment conçu pour l’ataxie, a été encore améliorée dans cette étude pour tenir compte des déficits de mouvement oculaire cliniquement observés dans les SCA. Avec une métrique aussi nuancée, un score BARS amélioré s’est révélé corrélé avec le stade, la gravité et la durée de la maladie, quel que soit le type d’ataxie.

Continue reading “Les yeux, des fenêtres pour voir la fonction cérébrale dans les ataxies spinocérébelleuses”