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/

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.

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El BDNF puede revertir la ataxia en ratones SCA1

Escrito por Anna Cook Editado por Dr. David Bushart. Publicado inicialmente en el 19 de Marzo de 2021. Traducción al español fueron hechas por FEDAES y Carlos Barba.

El factor neurotrófico derivado del cerebro -BDNF- puede prevenir la ataxia en ratones SCA1. Una nueva investigación muestra que el tratamiento funciona incluso si se inicia después de que los ratones desarrollan signos de ataxia.

SCA1 es una enfermedad neurodegenerativa causada por una mutación en el gen Ataxin1 . Las personas con SCA1 a menudo desarrollan síntomas alrededor de los 30-40 años, aunque esto puede variar. Los síntomas más comunes incluyen ataxia o problemas de movimiento que dificultan moverse y caminar. Estos síntomas empeoran progresivamente y eventualmente provocan problemas para tragar o hablar. Actualmente no existe cura para SCA1, por lo que es importante que se realicen investigaciones sobre posibles tratamientos.

El laboratorio de la Dra. Marija Cvetanovic de la Universidad de Minnesota ha estado utilizando un modelo de ratón de SCA1 para tratar de identificar nuevos tratamientos. En el pasado, estos investigadores han demostrado que una molécula llamada factor neurotrófico derivado del cerebro (BDNF) podría retrasar la aparición de ataxia en un modelo de ratón de SCA1.

A laboratory mouse sitting on a researcher's hand.
La investigación con ratones SCA1 muestra que el tratamiento con BDNF puede tener un impacto, incluso después de que comienzan a aparecer los síntomas de la ataxia.. Foto utilizada bajo licencia por unoL/

El BDNF es una molécula que se encuentra en el cerebro y es muy importante para el desarrollo saludable del cerebro. Es necesario para que muchos procesos del cerebro funcionen con normalidad. Los investigadores demostraron que los niveles de BDNF se redujeron en los cerebros de los ratones SCA1. Los investigadores inyectaron BDNF en los cerebros de estos ratones para intentar compensar el BDNF perdido. Este tratamiento, antes de que los ratones comenzaran a desarrollar síntomas de ataxia, previno la aparición de problemas motores y la muerte de las células de Purkinje.

Este trabajo anterior fue muy prometedor, pero había un problema. En este estudio, el tratamiento solo se probó antes de que los ratones SCA1 desarrollaran signos de problemas motores o cambios en sus cerebros. En el mundo real, si queremos ayudar a los pacientes con SCA1, necesitamos tratamientos que funcionen incluso una vez que la enfermedad haya comenzado a progresar. Por lo tanto, era importante que los investigadores averiguaran si este tratamiento funcionaría más adelante en la progresión de la enfermedad. Eso es exactamente lo que hicieron a continuación: en diciembre de 2020, el laboratorio de Cvetanovic publicó los resultados de su estudio que probaba el BDNF como tratamiento después de que los ratones habían comenzado a desarrollar signos de SCA1.

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BDNF can reverse ataxia in SCA1 mice, even after symptom onset

Written by Anna Cook Edited by Dr. David Bushart

Brain-derived neurotrophic factor can prevent ataxia in SCA1 mice. New research shows that the treatment works even if it’s started after mice develop signs of ataxia.

SCA1 is a neurodegenerative disease caused by a mutation in the Ataxin1 gene. People with SCA1 often develop symptoms around 30-40 years old, although this can vary. The most common symptoms include ataxia, or movement problems that make it difficult to move and walk. These symptoms get progressively worse, eventually leading to problems with swallowing or speaking. There is currently no cure for SCA1 so it is important that research is conducted into potential treatments.

The lab of Dr. Marija Cvetanovic at the University of Minnesota has been using a mouse model of SCA1 to try to identify new treatments. In the past, these researchers have shown that a molecule called brain-derived neurotrophic factor (BDNF) could delay the onset of ataxia in a mouse model of SCA1.

A laboratory mouse sitting on a researcher's hand.
Research using SCA1 mice shows that BDNF treatment can have an impact, even after ataxia symptoms begin showing. Photo used under license by unoL/

BDNF is a molecule found in the brain that is very important for healthy brain development. It is needed to keep many processes in the brain working normally. The researchers showed that levels of BDNF were reduced in the brains of SCA1 mice. The researchers injected BDNF into the brains of these mice to try to make up for the lost BDNF. This treatment, before the mice had begun to develop symptoms of ataxia, prevented the onset of motor problems and Purkinje cell death. You can read more about those findings in this past SCASource article.

This previous work was very promising, but there was one problem. In this study, the treatment was only tested before the SCA1 mice developed signs of motor problems or changes in their brains. In the real world, if we want to help SCA1 patients, we need treatments that will work even once the disease has started to progress. It was therefore important for the researchers to find out whether this treatment would work later in disease progression. That is exactly what they did next: In December 2020, the Cvetanovic lab published the results from their study testing BDNF as a treatment after mice had started to develop signs of SCA1.

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A new molecule identified that controls cerebellar communication

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

Targeting phosphatases in the cerebellum can correct miscommunication in multiple models of ataxia.

The cerebellum is essential for motor coordination and consists of the coordinated activity of different types of cells. Purkinje cells are one of the most fascinating cell types in the cerebellum. They have an elaborate network of branches called dendrites, where a neuron receives communication from other neurons. It is one of the most complex branching systems seen across all neurons in the entire brain. Each one of these branches has many points of contact with other branches called axons. Each axon is part of a neuronal structure that allow communication between neurons. These axons are from different cell types and allow information to be transferred to Purkinje cells.

Colourful illustration of a human brain
Targeting phosphatases in the brain could improve communication between neurons, reducing ataxia symptoms.

Due to this branching complexity, Purkinje cells receive many messages or inputs. This represents different pieces of sensory information to ensure that movements are precisely timed. Purkinje cells must integrate and process this information. This produces motor behaviors like walking, writing, playing a musical instrument, and many more. Any alteration to the processing of this information will result in cerebellum dysfunction; in fact, Purkinje cells have gained attention because they undergo progressive deterioration in most ataxias. 

Neurons, including Purkinje cells, communicate with other neurons using electrical signals known as action potentials or spikes. Firing rate, defined as the number of spikes within a defined period of time, is thought to be an important feature of this communication, which is critical for coordinating muscle movements. Therefore, a lower firing rate in Purkinje cells would signal a faulty communication between Purkinje cells and their targets. This has devastating consequences as seen in many ataxias.

For instance, in an earlier study, a group of authors found that the firing rate of Purkinje cells was decreased in mouse models of three different Spinocerebellar ataxias (SCAs): SCA1, SCA2, and SCA5. They further explored whether there was a common reason underlying the decreased firing rate. They found that a protein named Missing in Metastasis (MTSS1), was important for Purkinje cells to effectively communicate with each other. Mice engineered to have no MTSS1 protein had a decreased firing rate and difficulty walking and maintaining their balance.

In every cell in the body, including brain cells, there are numerous proteins that perform different functions. The concerted effort of all are needed for the cell to perform its intended duty. Some of these proteins are maintained in the cell in an inactive form and are activated when they are required in the cell and inhibited when they are not. This highly regulated system aims to maintain precise levels of proteins in each cell, while simultaneously conserving energy. Each cell has many ways of activating/inactivating a protein. A specialized group of proteins known as kinases and phosphatases, adds and removes phosphate groups to and from proteins respectively, thereby altering their active/inactive forms which then changes their interactions with other proteins. MTSS1 is one such protein that inhibits the activity of a group of kinases known as Src family of non-receptor tyrosine kinases (SFKs).

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Mutated ataxin-1 protein forms harmful, doughnut-shaped aggregates that are not easily destroyed

Written by Brenda Toscano Marquez   Edited by Marija Cvetanovic

Insoluble clumps of mutated ataxin-1 capture essential proteins and trigger the creation of toxic reactive oxygen species.

All proteins produced by our cells consist of long chains of amino acids that are coiled and bent into a particular 3D structure. Changes in that structure can cause serious issues in a cell’s function, sometimes resulting in disease. Spinocerebellar ataxia type 1 (SCA1) is thought to be the result of one such structural change. The cause of SCA1 is a mutation that makes a repeating section of the ATXIN1 gene abnormally long. This repeated genetic code, “CAG,” is what encodes the amino acid glutamine in the resulting ataxin-1 protein. Therefore, in the cells of patients with SCA1, the Ataxin-1 protein is produced with an expanded string of glutamines, one after the other. This polyglutamine expansion makes the mutated ataxin-1 protein form clumps in many different types of cells – most notably, though, in the cells most affected in SCA1: the brain’s Purkinje cells.

Recent research suggests that these clumps, or “aggregates,” not only take up space in the cell, but that the act of ataxin-1 proteins clustering together might even be beneficial in early stages of disease (it’s possible that the proteins wreak less havoc when they’re in large clumps, rather than all floating around individually). However, another line of research suggests that ataxin-1 aggregates might also be toxic, triggering signals that lead to the cell’s death. As such, how exactly these aggregates affect the deterioration of cells has remained an important question in SCA1 research.

n a search for answers, an international team led by Stamatia Laidou designed a unique cell model of SCA1 to track the development of ataxin-1 aggregates. Their study, published in a recent paper, made use of normal human mesenchymal stem cells that had been engineered to make a modified version of the ataxin-1 protein. In these cells, ataxin-1 was produced not only with the SCA1-causing expansion, but also with a marker protein attached to its end. This marker, known as “green fluorescent protein” (GFP), is used extensively in biological research because it glows under fluorescent light.

doughnut with white and pink sprinkles
Laidou and colleagues have observed mutated ataxin-1 clumps that cause cell stress. Photo by Tim Gouw on

Using this to their advantage, Laidou and her team used a fluorescent microscope to follow the formation of ataxin-1 aggregates over the course of 10 days. The abnormal protein first started accumulating in the nucleus as small dots. As time went on, these dots started blending together, increasing in size. By ten days, the ataxin-1 aggregates had grown even more, forming a doughnut-shaped structure that occupied most of the cell’s nucleus – a crucial structure that houses the cell’s genetic information. These results were intriguing, since the accumulation of normal, non-expanded Ataxin-1 protein does not result in an aggregate with a doughnut shape.

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