Arrival of SCA1-fish: Expanding the research tools to study Spinocerebellar ataxia type 1

Written by Dr. Marija Cvetanovic Edited by Dr. Larissa Nitschke

Elsaey and colleagues develop a new animal model of SCA1 using zebrafish. These SCA1-fish can help researchers learn more about what happens to neurons as disease progresses.

Spinocerebellar ataxia type 1 is dominantly inherited spinocerebellar ataxia caused by the lengthening of the polyglutamine repeats in the protein ataxin-1. Patients with SCA1 slowly lose their sense of balance, and can experience other symptoms like depression. Studies have shown that a key feature of SCA1 is the loss of Purkinje cells in the patient’s cerebellum.

 Since the discovery of SCA1 in 1993, the use of mouse and cell models of disease have really helped researchers understand how mutant ataxin-1 affects Purkinje cells to cause SCA1 symptoms. Each model has its advantages and disadvantages. You need to consider several things when picking which model to use to study SCA1, like cost and similarity to humans.

For example, mouse models of SCA1 are useful to study pathogenesis at the molecular, cellular, tissue, and behavioral levels. But mice are costly and can take a long time to develop. It is also difficult to study the loss of Purkinje cells in live mice. On the other hand, fruit fly models are relatively cheap and grow really quickly, which allows for high-throughput studies of how different genes affect SCA1. But since fruit flies are evolutionarily distant from humans and do not have a cerebellum, they cannot be used to study Purkinje cells loss.

A school of eight zebrafish swimming in front of a white background. They are 2.5 cm to 4 cm long and have blue stripes
Zebrafish are small freshwater fish that are a common model organism for scientific research. Photo used under license by Horvath82/Shutterstock.com.

This is why creating a SCA1 zebrafish model is exciting. Zebrafish have very similar cerebellar anatomy and function to mammals. Also, Zebrafish larval stages are almost transparent, allowing for non-invasive imaging. Zebrafish are also much more cost-effective than mice and are easier to modify.

Continue reading “Arrival of SCA1-fish: Expanding the research tools to study Spinocerebellar ataxia type 1”

Measuring neurodegeneration in spinocerebellar ataxias

Written by Dr Hannah K Shorrock Edited by Dr. Maria do Carmo Costa

Neurofilament light chain predicts cerebellar atrophy across multiple types of spinocerebellar ataxia

A team led by Alexandra Durr at the Paris Brain Institute identified that the levels of neurofilament light chain (NfL) protein are higher in SCA1, 2, 3, and 7 patients than in the general population. The researchers also discovered that the level of NfL can predict the clinical progression of ataxia and changes in cerebellar volume. Because of this, identifying patients’ NfL levels may help to provide clearer information on disease progression in an individualized manner. This in turn means that NfL levels may be useful in refining inclusion criteria for clinical trials.

The group enrolled a total of 62 SCA patients with 17 SCA1 patients, 13 SCA2 patients, 19 SCA3 patients, and 13 SCA7 patients alongside 19 age-matched healthy individuals (“controls”) as part of the BIOSCA study. Using an ultrasensitive single-molecule array, the group measured NfL levels from blood plasma that was collected after the participants fasted.

The researchers found that NfL levels were significantly higher in SCA expansion carriers than in control participants at the start of the study (baseline). In control individuals, the group identified a correlation between age and NfL level that was not present among SCA patients. This indicates that disease stage rather than age plays a larger role in NfL levels in SCAs.

Looking at each disease individually, the group was able to generate an optimal disease cut-off score to differentiate between control and SCA patients. By comparing the different SCAs, the research group found that SCA3 had the highest NfL levels among the SCAs studied. As such, SCA3 had the most accurate disease cut-off level with 100% sensitivity and 95% specificity of defining SCA3 patients based on NfL levels.

Artist's drawing of a group of Laboratory Scientist sturying a larger-than life human brain
A team from the Paris Brain Institute identify that SCA1, 2, 3, and 7 patients have higher levels of NfL protein than the general population. Photo used under license by ivector/Shutterstock.com.
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Snapshot: What is N-acetylcysteine?

What is N-acetylcysteine used for?

Cysteine is an amino acid that is used as a building block in our bodies to make proteins. We consume cysteine in our diets through protein-rich foods, like beef or lentils. N-acetylcysteine is a chemical derivative of cysteine. This means which means that N-acetylcysteine contains one change in its chemical structure that distinguishes it from cysteine. N-acetylcysteine is often taken as a supplement. It is also used clinically by doctors to treat patients experiencing acetaminophen ( also known as Tylenol or paracetamol) overdose and some respiratory conditions such as bronchitis.

Companies that sell N-acetylcysteine as a supplement claim that it can prevent or treat many health ailments, such as cancer, liver disease, diabetes, high cholesterol, and psychiatric disorders like depression. Some clinical trials have been conducted to test if N-acetylcysteine can truly help with these illnesses, but the results have been mixed and inconclusive.

Some of this variability could come from the way N-acetylcysteine was given to the participants (orally, nasally, or intravenously) and the dosage amount. While N-acetylcysteine is safe to consume, it’s worth noting that some participants in these trials have had more adverse effects than placebo groups. They weren’t serious, but usually consisted of nausea and headache.

White capsule pills spilling out of a percription bottle.
N-acetylcysteine is being tested to treat neurodegenerative diseases, but the clinical trial results have been mixed and inconclusive. Image used from Pxfule.

How does our body utilize N-acetylcysteine?

The main way N-acetylcysteine is thought to provide a therapeutic effect in the body is by acting as an antioxidant. Antioxidants are substances that prevent or slow the damage that can be caused to cells by free radicals, which are also known as reactive oxygen species. Free radicals are molecules that have an unpaired electron. This causes free radicals to be unstable because they want to “steal” an electron from a nearby molecule so that their unpaired electron will have a partner. If left unchecked, free radicals could damage cell components like lipids and nucleic acids (like DNA) through this process.

Fortunately, our body has antioxidant defenses to prevent this damage as they can neutralize free radicals. One of the main antioxidants our body uses is glutathione. To produce glutathione, a cysteine molecule is required. N-acetylcysteine can provide that cysteine to increase the levels of glutathione. This may be helpful for diseases where oxidative stress is involved in disease pathology, like in neurodegenerative or heart diseases. Oxidative stress occurs when there is an imbalance between free radicals and antioxidants, leading to an accumulation of free radicals.

Has N-acetylcysteine ever been tested as a treatment for Spinocerebellar ataxia (SCA)?

There have not been any clinical trials conducted to test the effect of N-acetylcysteine on any of the spinocerebellar ataxias. The only experimental data that exists is from a study in 2003 that used a cell model for SCA1, where researchers found that N-acetylcysteine had a positive effect on cell traits associated with SCA1. However, there have been some clinical trials in other neurodegenerative diseases. Oxidative stress in the brain is commonly seen in many neurodegenerative diseases, including many types of spinocerebellar ataxia and Parkinson’s disease.

Several clinical trials have been done in Parkinson’s disease to determine if N-acetylcysteine can help improve symptoms, but there have been some conflicting results that may be due to the way N-acetylcysteine was administered. When participants took N-acetylcysteine only orally, there was no effect on symptoms and brain scans did not show increased antioxidant levels. However, in a trial where oral was combined with intravenous administration, some positive effects on symptoms and biomarkers were found. You can learn more about this study at this link. More information about this study can be found here.

For now, we cannot make conclusions that N-acetylcysteine would have the same effect for all neurodegenerative diseases, but it does have potential that should be explored by researchers in spinocerebellar ataxias.

If you would like to learn more about N-acetylcysteine, take a look at this resource by the Memorial Sloan Kettering Cancer Center.

Snapshot written by Nola Begeja and edited by Dr. Gulin Oz.

“Expanding” the therapeutic promise for SCA1

Written by Dr. Judit M Perez Ortiz Edited by Dr. Maria do Carmo Costa

A druggable target in Spinocerebellar Ataxia type 1 (SCA1) shows promise in treating cerebellar and non-cerebellar aspects of disease.

Spinocerebellar Ataxia type 1 (SCA1) is a neurodegenerative disease that typically starts with coordination difficulties (ataxia) in mid- to late-adulthood, worsens over time, and shortens life expectancy. SCA1 runs in families, as it is caused by a genetic mutation in a gene called Ataxin-1. The gene’s instructions make a protein conveniently also termed “ataxin-1”. Healthy ataxin-1 is important in orchestrating important processes in brain cells. 

In SCA1, mutant ataxin-1 drives disease by affecting these important cellular processes. In patients with SCA1, their ataxin-1 protein has a polyglutamine repeat expansion mutation that makes the protein behave in toxic ways. The disarray caused by mutant ataxin-1 protein slowly deteriorates and ultimately compromises the health of the brain areas involved. Research on this topic is very rich and increasingly exciting. SCA1 treatments under investigation explore different strategies to minimize the insult caused by mutant ataxin-1.

New work by Nitschke and colleagues takes previous efforts a step further towards this goal by delving deeper into the promises and limitations of an exciting therapeutic “angle” in the ataxin-1 protein itself.

Experimental mice are placed on the rotating rod to animal test in the Laboratory
Research in SCA1 mice shows preventing S776 phosphorylation improved muscle strength, respiratory function, and prolonged lifespan. Photo used under license by unoL/Shutterstock.com.
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Snapshot: What is Riluzole?

Riluzole, often sold under the trade name Rilutek, is a medication used for the treatment of amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease that mainly affects neurons controlling muscle movements. The drug was approved by the FDA (1995), Health Canada (1997), and the European Commission (1996). It helps slow down disease progression and may extend patient survival. The medication is available in tablet and liquid form, generally well-tolerated. There are sometimes mild side effects, which may include loss of appetite, nausea, and abdominal pain.

Close up of a woman taking a pill with water
Riluzole has been used to treat ALS, and research has suggested it may also help with forms of ataxia. It is currently being tested in clinical trials. Photo used under license by fizkes/Shutterstock.com.

How does it work?

Exactly how Riluzole slows disease progression remains unknown. However, it is thought that its neuroprotective effects likely stem from reducing a phenomenon known as excitotoxicity.

Neurons communicate with each other through chemical messengers called neurotransmitters. The signalling of these messengers needs to be tightly controlled. Too little or too much signaling will disrupt normal functions of the brain and cause damage to cells. Excitotoxicity is the result of excessive signaling by glutamate, one of the most abundant neurotransmitters in the brain. Glutamate is also associated with many neurodegenerative diseases.

Riluzole prevents this excessive signaling through several mechanisms. It is hypothesized that the effectiveness of riluzole in ALS treatment is the result of this neuroprotective property.

Riluzole for Ataxia

The neuroprotective function of riluzole has been a point of interest for the treatment of other neurodegenerative diseases since its approval. Multiple clinical trials have been conducted for patients with neurodegenerative diseases including Parkinson’s disease, Huntington’s disease, multiple system atrophy, and ataxia.

In 2010, a pilot trial was conducted with 40 patients with cerebellar ataxia who showed a lower level of motor impairment, measured by the International Cooperative Ataxia Rating Scale. A follow-up trial was then performed in 2015 for 55 patients with spinocerebellar ataxia (SCA) or Friedreich’s ataxia. Similarly, patient impairment had improved by an alternative measurement using the Scale for the Assessment and Rating of Ataxia. These findings indicate the possibility of riluzole being an effective treatment for cerebellar ataxia. However, more long-term studies and ones that are specific to different types of SCA need to be conducted to confirm the results.

Riluzole in Development

Even though riluzole was discovered more than 25 years ago, variations of the drug are still under development. As ALS often affects a patient’s ability to swallow, a new formulation of riluzole that is absorbed by placing it under your tongue is being developed under the name Nurtec.

Another prodrug version of riluzole, named Troriluzole (BHV-4157), may be better absorbed by the body with fewer side effects. Troriluzole is currently in phase three clinical trial for patients with different types of SCA. The trial is expected to be complete by November 30, 2021, and will hopefully provide more insight into the effectiveness of Troriluzole in SCA patients.

If you would like to learn more about Riluzole, take a look at these resources by the ClinicalTrials.gov and the Mayo Clinic.

Snapshot written by Christina (Yi) Peng and edited by Terry Suk.