Tag: Zebrafish

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”

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.

Continue reading “Non-invasive imaging of neurodegeneration in live animals”