Recovering Purkinje cell health could improve quality of life in SCA3

Written by Jorge Diogo Da Silva Edited by Dr. David Bushart

Normalizing neuronal dysfunction in SCA3/MJD by activating a receptor inside cells

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an inherited neurodegenerative disease that typically begins in mid-adulthood. This disease causes loss of coordination and balance (a group of symptoms known as ataxia), abnormal eye movements, and other motor symptoms, all of which limit a patient’s daily life activities. Treating SCA3 patients is currently very challenging, since there are no drugs or other treatments that slow or stop the progression of this disease. While several therapeutic options have been tested in clinical trials, none have shown considerable and consistent effects in improving disease symptoms. Therefore, it is imperative that other treatments are investigated and tested in the clinical setting, in the hopes that we might find a way to improve the lives of SCA3 patients.

The cause of this disease is very well-characterized: patients with SCA3 have an abnormal form of a protein called ataxin-3. All proteins are made up of a sequence of several smaller building blocks known as amino acids. In ataxin-3’s sequence, there is a region where one type of amino acid, glutamine, is repeated consecutively. SCA3 arises when the number of these repeated amino acids is very high (an abnormality known as a polyglutamine expansion), which is toxic for cells.

One of the regions of the brain that is most responsible for regulating balance and movement coordination is the cerebellum, which is located just behind the brainstem (the region connecting the spinal cord to the rest of the brain). As expected, the cerebellum is one of the most affected brain regions in SCA3, since it helps control gait and coordination. Purkinje cells, which are some of the largest neurons in the brain, make up a substantial portion of the cerebellum. These cells receive information from other neurons that detect our surroundings, then emit a signal to the brain regions that control muscles and regulate our movement. This allows us to make movements that are coherent and fluid.

cross section of the cerebellum with purkinje cells stained blue
Cerebellum Cross Section with Purkinje Cells. Image courtesy of Berkshire Community College Bioscience Image Library

Since Purkinje cells are dysfunctional in SCA3, it is reasonable to think that improving the well-being of these cells could also reduce symptoms. In a recent publication, Watanave and colleagues described how they explored a strategy to improve Purkinje cell function using drugs in a mouse model of SCA3, with findings that could be relevant for future studies in patients.

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Non-invasive imaging of neurodegeneration in live animals

Written by Dr. Marija Cvetanovic   Edited by Larissa Nitschke

Purkinje cells (a type of neuron in the cerebellum) are the most vulnerable cells in many Spinocerebellar Ataxias (SCAs). While animal models of SCA have been very fruitful in understanding the mechanisms of Purkinje cell neurodegeneration, none of these models have allowed for visualization of neurodegenerative processes in live animals as the disease progresses – until now. In the laboratory of Dr. Reinhard Köster, researchers have developed a zebrafish model of SCA that allows for the expression of SCA-causing mutant protein in Purkinje cells and proteins that can be used to monitor Purkinje cell changes. As zebrafish larvae are almost transparent, researchers can now study pathogenic changes in neurons in a live animal during disease progression.

Since the 1993 discovery of the mutation that causes Spinocerebellar Ataxia Type 1 (SCA1), we have significantly increased our understanding of disease pathogenesis using animal models. While there are advantages and disadvantages of using any model, most researchers would agree that the similarity between humans and the animal used, plus the cost of creating and caring for the animals, are critical determinants of which model to choose. Mouse models, for instance, are useful to study pathogenesis at the molecular, cellular, tissue and behavioral level, but are costly to house and maintain. Fruit fly models, on the other hand, allow high-throughput studies (that is, studies that can produce a lot of relevant data quickly) of disease modifying properties but are much farther from human beings evolutionarily. Unfortunately, neither of these animal models allow us to follow up changes in neurons in the same animal throughout disease progression – to study the neurons, the animal must be euthanized and the brain must be dissected. Understanding how neurons are affected during disease progression, however, is very important. Observing the same neurons over time could increase our understanding of disease processes and inform us about the optimal timing for therapies. For example, if we were to identify changes in neurons that occur just prior to the onset of motor symptoms, this might mean that these changes are a contributing factor to behavioral pathology. This could also tell us the stage at which neurons start dying and disease thus becomes irreversible.

In an effort to examine how cells behave over time, many researchers use zebrafish. The fact that zebrafish embryos (larvae) are mostly transparent means that we can follow changes in neurons throughout disease progression. Moreover, in most SCAs, Purkinje cells in the cerebellum are the neurons that are most affected by the disease-causing mutant protein, and the zebrafish cerebellum has an anatomy and function that is quite similar to the human cerebellum. Zebrafish are also inexpensive and produce hundreds of offspring weekly, providing researchers with a large number of animals to study.

A dozen zebrafish swim in deep blue water. Zebra fish are narrow and long. They have two to three black stripes running down their side.
A school of Zebrafish (Photo by Lynn Ketchum, courtesy of Oregon State University)

Using state-of-the-art genetic approaches, Dr. Reinhard Köster’s laboratory at the Technical University of Braunschweig in Germany created a zebrafish model of SCA that expresses two types of protein in their Purkinje cells: a disease-causing SCA mutant protein, and a fluorescent reporter protein to monitor degenerative changes and cell death.

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Brain-derived neurotrophic factor: A new (old) hope for the treatment of SCA1

Written by Eviatar Fields Edited by Dr. Vitaliy Bondar

Scientists use Brain Derived Neurotrophic Factor to delay motor symptom onset and cell death in a mouse model of Spinocerebellar Ataxia Type 1

Spinocerebellar ataxia type 1 (SCA1) is a rare neurodegenerative disease that affects about 2 out of 100,000 individuals. Patients with SCA1 present with motor symptoms such as disordered walking, poor motor coordination and balance problems by their mid-thirties and will progressively get worse symptoms over the next two decades. No treatments for SCA1 exists. These motor symptoms cause a significant decrease in patient independence and quality of life. Scientists use mouse models that recreate many SCA1 symptoms to understand the cause of this disease and test new treatments.

In this paper, Mellesmoen and colleagues use a mouse model of SCA1 which presents with severe motor symptoms by adulthood. In order to measure the severity of the motor problems in the SCA1 mouse model, the researchers use a test called a rotarod. The rotarod test is similar to a rolling log balance: mice are placed on a rotating drum that slowly accelerates. Mice that can stay on the drum for longer durations have better motor coordination than mice who fall off the drum earlier. Mellesmoen was trying to find a way to get the mice to stay on the drum for longer.

artistic cartoon of male doctor sin from of a microscope and large DNA model
Cartoon of a medical researcher holding a clipboard. 

Purkinje cells, the main cells of the cerebellum, eventually die in SCA1 mouse models and in patients later in life. However, it remains unclear how and why these brain cells, which are responsible for the fine-tuning of movement and motor coordination, die. This is an important question as its answer might lead to new treatments that prevent brain cells from dying which might improve SCA1 symptoms. One possibility is that some changes in gene expression (that is, how “active” or “inactive” a gene is) causes the cells to die in SCA1 mice. To test this hypothesis, the authors used a technique called RNA-seq to examine how gene expression is altered in SCA1 mice compared to healthy mice.

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Discovery in mice sheds light on how the brain learns to adjust how we walk (video)

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

New research identifies the cell type in the cerebellum that is vital for a specific form of motor learning

Locomotion – the process of moving oneself from one place to another – is highly adaptive. Depending on our current needs, we can alter the way we walk (known as our gait) without much trouble. For instance, we might increase our speed to get to a meeting in time or, if we have time for a more relaxing stroll, reduce our speed. This locomotor adaptation may seem effortless, but it actually involves a high level of coordination. It is quite apparent when witnessing a toddler trying to walk that figuring out our adaptive mechanisms plays an important role in fine-tuning movements. Because of this, determining how locomotor adaptation works has become a focus of research in the field of rehabilitative therapy, especially with patient populations that experiences gait deficits.

Young toddler boy learning how to walk and balance
Photo of a toddler how to walk. How does of brain learn how to fine tune our movements to help us balance? Photo by Aleksandr Balandin on Pexels.com

In an effort to better understand the intricate details of locomotor adaptation, researchers at the University of Portugal recently performed a study using adult mice. In this study, mice performed a task on a specialized piece of equipment called a split-belt treadmill, which consists of two separate belts running parallel to each other. The speed of these belts can be independently controlled, allowing researchers to impose different demands to the limbs on the right side of the body versus the left. Though split-belt treadmills are used in rehabilitative therapy for patients with post-stroke hemiparesis (where one side of the body is weakened after stroke), this was the first study that adapted the use of this treadmill for mice.

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In search of a common pathway leading to motor dysfunction in cerebellar ataxias

Written by Dr. Carolyn J. Adamski Edited by Dr. Judit M Perez Ortiz

A research group uncovers a drug target to potentially correct motor phenotypes across several cerebellar ataxias.

When someone is diagnosed with spinocerebellar ataxia (SCA), their symptoms may look very similar despite the fact that different genes are causing the disease. There are over 35 genes known to cause cerebellar ataxia, each of which are studied by scientists to try to understand the ways in which they can each lead to disease. Increasingly, scientists are beginning to appreciate that perhaps it would be helpful to find commonalities between the different SCAs to identify treatment options that could help more SCA patients. The emerging picture is that the genes causing cerebellar ataxia are all vital to the health and function of neurons. Studies like these are currently being conducted all over the world. One group focused on MTSS1, a critical component of neuronal function. They made the exciting discovery that a handful of other genes known to cause cerebellar ataxia were doing so, at least in part, through MTSS1. This study uncovered a common network between cerebellar ataxia genes. Their hope is that someday clinicians will be able to treat many cerebellar ataxias with one therapy.

wooden pole with a wooden arrow pointing to the left
A photo of a road sign giving direction. Could MTSS1 be the pathway sign pointing towards ataxia? Photo by Jens Johnsson on Pexels.com

One approach scientists use to understand a gene’s function is to remove it from the genome, typically in mice, and observe what happens. This group reported that when they removed MTSS1, mice were not able to walk as well as healthy mice. This defect got progressively worse with age. What they observed in these mice looked very similar to what patients with cerebellar ataxia experience. Because there are a few areas of the brain important for walking, the authors wanted to make sure this was due to defects in the cerebellum. Neurons in the cerebellum missing MTSS1 were there, but they were unable to effectively communicate with other neurons in the brain and were slowly dying. When a neuron in the cerebellum fails to communicate the right message, things like poor coordination of body movement happen.

After establishing that removal of MTSS1 causes disease, this group went back to the literature and found that MTSS1 was a fundamental regulator of a pathway known to be critical for communication between neurons. They looked in the mice lacking MTSS1 and found that this pathway was abnormally in “overdrive”. They immediately started looking for ways to correct this. They hoped that by correcting this major pathway, they could help the neurons to more effectively communicate body movements again. Eventually, they found a compound that could specifically dial this pathway down. They gave this drug to the mice lacking MTSS1 and used a number of tests to examine their every movement. To their surprise, they were unable to tell the difference between normal healthy mice and those lacking MTSS1 and treated with the compound. In other words, the compound was able to help the ataxia in these mice. This was an exciting result indeed!

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