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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Aperçu Rapide: Qu’est-ce que l’ataxie récessive ?

Qu’est-ce qu’un trouble récessif ?

Un trouble récessif est un trouble qui a un mécanisme de maladie spécifique. Pour qu’un trouble récessif se produise, les deux copies du gène responsable doivent être mutées pour qu’un patient présente des symptômes. Les ataxies qui suivent ce mécanisme de la maladie sont connues sous le nom d’ataxie récessive. Cependant, le fait d’avoir une mutation dans une seule copie du gène n’entraîne pas de trouble. Comme les personnes ne possédant qu’une seule copie mutée du gène peuvent transmettre le gène défectueux, ces personnes sont connues comme étant des porteurs non affectés. Les ataxies récessives varient en symptômes et en gravité, mais sont liées par leur mécanisme pathologique. Bien qu’aucun des ataxies cérébelleuses spinocérébelleuses (ACS) ne soit récessif, il existe plusieurs types d’ataxies récessives, dont l’ataxie cérébelleuse récessive autosomique de type 1 et 2 (ARCA1 et ARCA2), l’ataxie spastique récessive autosomique de Charlevoix-Saguenay (ARSACS), l’Ataxie de Friedreich, et l’ataxie des telangiectasie de la région de l’Ataxia. Par exemple, l’ataxie de Friedreich est causée par une expansion répétée des trinucléotides dans le gène de la frataxine (FXN). Les personnes qui n’ont qu’une seule copie élargie du gène FXN ne présentent aucun symptôme, tandis que les personnes qui ont deux copies élargies du gène FXN sont affectées par l’ataxie de Friedreich.

Comment les ataxies récessives sont-elles héritées ?

Pour chaque gène de notre corps, nous en avons deux copies, l’une héritée de notre mère et l’autre de notre père. Les deux parents d’une personne atteinte doivent avoir au moins une copie de la mutation pour qu’un enfant naisse avec un trouble récessif. Si les deux parents ne sont pas porteurs de la maladie, chaque enfant aura 1 chance sur 4 d’en être atteint.

Pour un patient atteint d’ataxie récessive, les chances d’avoir un enfant atteint du même trouble sont faibles. Pour qu’un patient transmette la maladie, son conjoint doit avoir au moins une copie mutée du gène responsable. Dans le cas où le conjoint d’un patient est porteur, les enfants ont une chance égale d’être porteurs non affectés ou d’être affectés par la maladie. Cependant, les taux de porteurs de l’ataxie sont faibles dans la population, ce qui rend peu probable que le conjoint d’un patient soit également porteur de la mutation ataxique.

Image montrant les chances statistiques que deux parents porteurs non infectés transmettent un gène muté (25% enfant non affecté, 50% enfant porteur, 25% enfant affecté) ou un parent et porteur non affecté affecté (50% enfant porteur, 50% enfant affecté)
Comment les troubles récessifs sont héréditaires. Image d’Eder Xhako, créée avec BioRender

Comment un patient peut-il éviter de transmettre un trouble récessif à ses enfants ?

Généralement, lorsqu’un patient atteint d’ataxie récessive transmet la maladie à ses enfants, son conjoint est un porteur non affecté. Si vous êtes un patient atteint d’une forme d’ataxie récessive et que vous songez à avoir des enfants, votre conjoint peut subir un test de dépistage du porteur pour savoir s’il est porteur de la même ataxie récessive. Cela déterminera la probabilité que l’ataxie récessive soit transmise à vos enfants. S’il est établi que le conjoint est porteur, des options comme la FIV avec dépistage embryonnaire peuvent aider les patientes à prévenir la transmission de l’ataxie récessive à leurs enfants.

Si vous souhaitez en savoir plus sur les expansions répétées de trinucléotides, vous pouvez jeter un coup d’œil à notre dernier article sur l’expansion de la polyglutamine.

Si vous souhaitez en savoir plus sur le dépistage des porteurs et des embryons, jetez un coup d’œil à ces ressources du American College of Obstetricians & Gynecologists and Integrated Genetics.

Écrit par Eder Xhako, Édité par Larissa Nitschke. Traduction française par: L’Association Alatax, Publication initiale: 29 novembre 2019.

Designing a new “measuring stick” for ARSACS

Written by Dr. Brenda Toscano Márquez  Edited by Dr. Ray Truant

ARSACS researchers develop a better “measuring stick”, or disease severity index that can help better assess the progression of motor symptoms and compare different groups of ARSACS patients.

How does your doctor know you are sick? In short: measurements. Doctors record your weight, blood pressure, temperature, glucose levels, etc. The complex relationship between these biomarkers should indicate if you are healthy, or if not, to what degree you deviate from the healthy range.

Of course, each disease has a unique set of symptoms and characteristics. Performing the right measurements, with the right scales, is key to determining the type of disease, the course of treatment and most importantly, to know if the treatment is working. It would be careless and even dangerous if, for example, your doctor weighed you with a scale that could only detect a change of 10 kilograms. Even worse would be to focus on this measurement when you are actually suffering from high blood pressure.

yellow measuring tape wrapped up in ball
Photo by Marta Longas on

Patients with cerebellar ataxia also need physicians to perform the right measurements that take into account their particular type of ataxia. Proper measurements show how fast symptoms are progressing and if treatments and therapies are having an effect. Cynthia Gagnon and colleagues published a paper in the journal of Neurology this past year in which she and her collaborators designed a new set of measurements or “disease severity index” to track the symptoms better. The new index is designed for adult patients with a type of cerebellar ataxia called ARSACS. The researchers hope that this new index which they call DSI-ARSACS will help clinicians better assess how the disease is progressing, and will provide the means to compare different groups of patients.

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Snapshot: What is recessive ataxia?

What is a recessive disorder?

A recessive disorder is one that has a specific disease mechanism. For a recessive disorder to occur, both copies of the causative gene must be mutated for a patient to show symptoms.  Ataxias that follow this disease mechanism are known as recessive ataxia. However, having a mutation in only one copy of the gene does not lead to a disorder. As people with only one mutated copy of the gene can pass on the defective gene, these people are known as an unaffected carrier. Recessive ataxias range in symptoms and severity but are linked by their disease mechanism. While none of the Spinocerebellar Ataxias (SCAs) are recessive, there are many types of recessive ataxias, including Autosomal Recessive Cerebellar Ataxia Type 1 and 2 (ARCA1 and ARCA2), Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), Friedreich’s Ataxia, and Ataxia Telangiectasia. For example, Friedreich’s Ataxia is caused by a trinucleotide repeat expansion in the frataxin (FXN) gene. People with only one expanded copy of the FXN gene do not show any symptoms, while people with two expanded copies of the FXN gene are affected by Friedreich’s Ataxia.

How are recessive ataxias inherited?

For every gene in our body, we have two copies, one that is inherited from our mother and one from our father. Both parents of an affected individual have to have at least one copy of the mutation for a child to be born with a recessive disorder. If both parents are unaffected carriers, each child will have a 1 in 4 chance of getting the disorder.

For a patient affected with a recessive ataxia, the chances of having a child affected by the same disorder are low. For a patient to pass on the disease, their spouse must have at least one mutated copy of the causative gene. In the case where a patient’s spouse is a carrier, children have an equal chance of being an unaffected carrier or being affected by the disease. However, carrier rates for ataxias are low in the population, which makes it unlikely that a patient’s spouse is also a carrier for the ataxia mutation.

Map showing the statistical chance of two unnafected carrier parents passing on a mutated gene (25% unaffected child, 50% carrier child, 25% affected child) or an affected parrent and unaffected carrier (50% carrier child, 50% affected child)
How recessive disorders are inherited. Image by Eder Xhako, created with BioRender

How can a patient prevent passing on a recessive disorder to their children?

Generally, when a patient with recessive ataxia passes on the disorder to their children, their spouse is an unaffected carrier. If you are a patient with a form of recessive ataxia and are thinking about having children, your spouse can undergo carrier testing to find out if they are a carrier for the same recessive ataxia. This will determine the likelihood that the recessive ataxia is passed on to your children. If it is determined that the spouse is a carrier, options like IVF with embryo screening can help patients prevent passing on recessive ataxia to their children.

If you would like to know more trinucleotide repeat expansions, you can look at our past Snapshot on Polyglutamine Expansion.

If you would like to learn more about carrier and embryo screening, take a look at these resources by the American College of Obstetricians & Gynecologists and Integrated Genetics.

Snapshot written by Eder Xhako and edited by Larissa Nitschke.

Hunting for a needle in a haystack: Scientists identify the gene that causes ARSACS

Written by Dr. Sriram Jayabal Edited by Dr. Brenda Toscano-Marquez

Scientists uncover SACS, a gene containing the largest exon identified in vertebrates, which leads to ARSACS when mutated.

What is your morning routine? Coffee first, right? Now, try to think of all the diverse movements you need to make to accomplish this routine. For instance, just to get a cup of coffee, you have to complete a sequence of motor tasks: you start by pulling the pot out of the machine, then you walk to the tap, fill the pot with water, walk back, pour the water into the machine, put your coffee in, and then finally turn on the machine.

needle in haystack
Picture courtesy of Pixabay

To perform any of these movements, your brain needs to communicate with dozens of muscles in your body. Unfortunately, in people who are affected by hereditary ataxias, the brain loses the ability to coordinate these precise movements. These diseases primarily affect the way patients walk (the symptom that defines “ataxia”), eventually forcing them to use a wheelchair for the rest of their lives.

Hereditary ataxias can be broadly classified as either dominant or recessive. Dominantly-inherited ataxias can be passed down even if only one of the parents is affected; therefore, the disease does not skip generations. Recessive ataxias are inherited from parents who are both carriers of the disease mutation (and who do not usually show any symptoms). Therefore, recessive ataxias can skip generations.

One such recessive ataxia is called Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS). It was first discovered in people from the Charlevoix-Saguenay-Lac-Saint-Jean region of Quebec, Canada [1]. In this region, it is estimated that one out of every 22 individuals is a carrier for the disease mutation [2]. Though prevalent in this specific area of Canada, ARSACS has now been identified all across the world. Symptoms usually start in early childhood when toddlers are learning to walk. These children experience stiffness in the legs (spasticity) and incoordination in their gait (ataxia), leading them to fall more often. They also have difficulties writing, speaking, and performing tasks that require manual dexterity (usually actions that involve hand movements, like reaching for and grasping an object). They continue to experience worsening gait as they age, often needing a cane or handrail to move around by the time they reach adolescence. Around this time, many patients also experience retinal hypermyelination (an eye abnormality) and peripheral neuropathy (damage to the nerves throughout the body). By their thirties, they become dependent on a wheelchair. There is currently no cure for ARSACS, so it is imperative to study this disease’s underlying causes to identify effective treatments.

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