SCA8 Archives |

Working with cerebellar ataxia

Written by Dr. David Bushart Edited by Dr. Sriram Jayabal

How can employment be made more accessible for ataxia patients? What barriers exist? A study of workers and non-workers with ataxia analyzes the benefit of employment, as well as how to reduce risk of injury.

A job can often become part of a person’s identity. When people meet for the first time, one of the first questions that often comes up is “what do you do for work?” While this question can be harmless, it can also be frustrating to non-workers, particularly to those who are actively looking for employment. This may include some patients with cerebellar ataxia.

It can be difficult to manage disease symptoms alongside the stress of a job. However, some patients may find that including a job as part of their routine can be helpful for physical and mental wellness. In these cases, it is important for ataxia patients to have access to fair employment. Despite these benefits, finding a job can prove quite challenging, and unfortunately, ignorant assumptions about the capabilities of workers with ataxia may make finding employment even harder. How can employment be made more accessible to ataxia patients who wish to work?

two people shaking bands over a business agreement — Photo by fauxels on Pexels.com

Determining the work capabilities of ataxia patients

Helping ataxia patients find work might have a significant benefit on their overall quality-of-life. Researchers in Italy designed a study to get a better idea about the capabilities of workers with ataxia and the barriers to employment that they face. The research team, led by Alberto Ranavolo, interviewed both workers and non-workers with ataxia. Importantly, the patients interviewed for this study had been diagnosed with different types of ataxia, including dominantly-inherited ataxias, Friedrich’s ataxia, and other ataxias with unknown causes. Within this group, 24 were currently workers and 58 were non-workers at the time of the study. This allowed the researchers to determine how characteristics such as age, gender, education, and duration of symptoms might impact the ability to work.

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Eyes: Windows to peek at brain function in spinocerebellar ataxias

Written by Dr. Sriram Jayabal Edited by Dr. David Bushart

Eye movement deficits occur ubiquitously in spinocerebellar ataxias, even at early disease states, highlighting their clinical importance.

Imagine the different motor movements that you make in your everyday life. Many people think of actions that we perform using our hands and legs, such as reaching for objects or walking. Let’s zoom in on a different task: catching a baseball. You need to know where the ball is going to land so you can run to that spot, then guide your arms while diving, if need be, to catch the ball. For this to work perfectly, you need to see and follow the ball. Your eyes enable you to track the ball while it is moving. How can your eyes keep the ball in focus while you are running at full speed towards the spot where you expect the ball to land? Your eyes are equipped with muscles which enable the eyes to move so as to keep the visual scene in focus. These eye movements, as demanded by the needs of the current scenario, in this case, catching a baseball, are indispensable for us to see the world without any hindrance.

Woman with hand in a "C" shape in front of her face. She's focusing in on her eye. — The eyes may provide a window into spinocerebellar ataxia, even before other symptoms show up. Photo by fotografierende on Pexels.com

Which brain region gives us the power to do this?

The cerebellum, or “little brain”, which enables one to move their arms and legs precisely, also controls the way we move our eyes. Therefore, it is logical to posit that when cerebellum goes awry, it may lead to eye movement abnormalities. Several previous studies have shown this to be true in many spinocerebellar ataxias (SCAs), where non-gait symptoms such as eye movement abnormalities have been found to accompany gait deficits in advanced stages of the disease. However, recent work from pioneers in clinical ataxia research at the Harvard Medical School have shown that eye movement abnormalities are also commonly present in SCAs even in pre-symptomatic states. This study emphasizes the critical need to better document the history of eye movement deficits and track them throughout the progression of the disease. This will help researchers to develop better rating scales for ataxia.

In this study, a population of SCA patients (134 individuals) who exhibited different types of SCA (including SCA1, SCA2, SCA3, SCA5, SCA6, SCA7, SCA8 and SCA17) were assessed for eye movement abnormalities at different stages of the disease, from pre-symptomatic (with no gait deficits) to advanced stages (those who use a wheel-chair). First, it was found that ~78% of all pre-symptomatic individuals exhibited eye movement deficits, and these deficits became even more common as the disease progressed, where every single person in advanced stages exhibited eye movement deficits. Second, when researchers examined the eye movements closely, they found that different types of ataxia might cause different kinds of eye movement deficits. However, these results are only suggestive because of the small population size of early-stage SCA individuals in this study, and the types of assessments used. Therefore, future studies will require a larger population size and a thorough quantitative analysis of specific types of eye movement deficits to help characterize eye movement abnormalities in SCAs. Finally, the Brief Ataxia Rating Scale (BARS), a recently designed simple clinical test for ataxia, was further improved in this study to account for the clinically observed eye movement deficits in SCAs. With such a nuanced metric, an improved BARS score was found to correlate with the stage, severity and duration of the disease irrespective of the type of ataxia.

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Snapshot: What is RAN translation?

In many diseases caused by repeat expansion mutations in the DNA, harmful proteins containing repetitive stretches are found to build up in the brain. The repeat expansion mutation, when translated into a protein, results in an abnormally expanded repeat tract that can affect the function of the protein and have harmful consequences for the cells. Following a study published in 2011, we know that repeat expansion mutations can make additional harmful repeat-containing proteins by a process called Repeat Associated Non-AUG translation or RAN translation.

How are proteins made?

To get from DNA to protein, there are two main steps. The first step involves the conversion of a gene in the DNA into an instructional file called messenger RNA (mRNA). The second step is translation, this is where the cellular machinery responsible for making proteins uses mRNA as a template to make the protein encoded by the gene.

During translation mRNA is “read” in sets of three bases. Each set of three bases is called a codon and each codon codes for one amino acid. There is a specific codon that signals where to start making the protein, this codon is AUG. From the point where the cellular machinery “reads” the start codon, the mRNA is “read” one codon at a time and the matching amino acid is added onto the growing protein.

What happens when there is a repeat expansion mutation?

As the name suggests, Repeat Associated Non-AUG (RAN) translation is a protein translation mechanism that happens without a start codon. RAN translation occurs when the mRNA contains a repeat expansion that causes the mRNA to fold into RAN-promoting secondary structures. Because RAN translation starts without an AUG start codon, the mRNA can be “read” in different ways.

Let’s consider a CAG repeat expansion to illustrate this process. In the CAG “reading frame” a polyglutamine containing protein would be made because the codon CAG leads to incorporation of the amino acid glutamine. But a CAG repeat expansion could also be “read” as an AGC or a GCA repeat expansion if you don’t know where in the sequence to start “reading”. When “read” as AGC, the cellular machinery would incorporate the amino acid serine, making a polyserine repeat protein. In the GCA frame a polyalanine repeat protein would be made. This has been shown to happen in Huntington’s disease (HD). In HD, RAN-translated polyserine and polyalanine proteins accumulate in HD patients’ brains, along with the AUG-initiated mutant huntingtin protein containing a polyglutamine expansion.

Diagram show how different DNA sequences can be "read" and translated as different proteins — Overview of repeat proteins that can be produced by RAN-translation from a CAG expansion transcript. Designed by Mónica Bañez-Coronel.

To complicate matters more, RAN translation can happen from different repeat expansions, including those in regions of the DNA that aren’t normally made into proteins at all. Through the process of RAN translation, repeat expansion mutations in the DNA can give rise to multiple different proteins that aren’t made in healthy individuals. RAN proteins have now been identified in several neurodegenerative diseases where they have been shown to be toxic to cells, including in HD, spinocerebellar ataxia type 8, myotonic dystrophy type 1 and 2, and C9orf72 amyotrophic lateral sclerosis (ALS).

To learn more about the implications of RAN proteins for repeat expansion diseases see this article by Stanford Medicine News Center.

To learn more about the process of translation see this article by Nature.

https://www.nature.com/scitable/topicpage/translation-dna-to-mrna-to-protein-393/

For the original article describing RAN translation see this article by PNAS, and this article by Neuron about RAN translated proteins in Huntington’s disease.

Snapshot written by Dr. Hannah Shorrock and edited by Dr. Mónica Bañez-Coronel.

The Discovery of SCA8

Written by Dr. Hannah K Shorrock Edited by Dr. Judit M Perez Ortiz

How one team uncovered the first SCA known to be caused by a CTG repeat expansion mutation

Identifying the gene that causes a type of ataxia not only gives patients and their families a clearer diagnosis and prognosis, but also allows scientists to model the disease. Through genetic animal models of ataxia, researchers can study how a single mutation causes a disease and how we can try to slow, halt, or even reverse this process. It is this path through research that may eventually lead from gene discovery to the development of effective therapies.

The gene that causes spinocerebellar ataxia type 8 (SCA8) was first described in a research article published in 1999. Since then, many research articles on SCA8 have been published, including research into the DNA repeat expansions that cause the ataxia, the cellular processes that lead to ataxia, and the development of multiple animal models of SCA8. Together, these move the scientific community further along the road of research.

mother with her two children looking at a mountain — Image of mother with her children. SCA8 was initially identified in a mother and daughter. SCA8 also shows maternal penetrance bias. Photo by Josh Willink on Pexels.com

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