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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Connecting the dots between genetics and disease in SCA13

Written by Dr. David D. Bushart  Edited by Dr. Carolyn J. Adamski

How one research group worked to identify previously unknown causes of SCA13, and what we can learn from their strategy.

With so many different causes of cerebellar ataxia, how are doctors able to make an accurate diagnosis? This is an extremely important question for doctors, research communities, and patients. For doctors, knowing the underlying genetic cause for a case of ataxia is critical not only for formulating a more specific treatment plan, but also for performing informed genetic screens to determine if a patient’s family members are at risk for developing ataxia. For researchers, knowing what causes a certain type of ataxia allows for the development of new treatment strategies. And for patients, an accurate diagnosis can, importantly, provide peace-of-mind.

Unfortunately, getting to this point of diagnosis can still be a difficult task in a lot of cases – up to 20 percent of ataxia cases do not have a confirmed genetic cause (Hadjivassiliou et al., Journal of Neurology, Neurosurgery, and Psychiatry 2016). This is clearly an area for improvement in the field of ataxia research. Fortunately, many research groups are making efforts to improve our knowledge of the many different causes for cerebellar ataxia, how frequently they appear, and how we might be able to better treat them.

two puzzle pieces being connected together by hands
Two puzzle pieces being connected together, much like how researchers connect pieces of data together to understand disease. Photo by Pixabay on Pexels.com

Though there are many studies that are continuously being performed and are constantly improving our knowledge of the specific causes of cerebellar ataxia, this summary will focus on the work of one group (Figueroa et al., PLoS One 2011). The research team, led by Dr. Stefan Pulst at the University of Utah, sought to better identify the frequency of different genetic mutations causing SCA13, a rare, dominantly-inherited form of spinocerebellar ataxia caused by mutations in a gene called KCNC3.

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