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”

¿Qué es el nistagmus?

El nistagmus, también conocido como ataxia ocular, es un término que se refiere al movimiento incontrolable del ojo, generalmente un ciclo repetitivo de movimiento lento en una dirección específica seguido de un ajuste rápido de regreso al centro. La raíz de este movimiento reside en un reflejo normal que usamos todos los días: el reflejo vestibulo-ocular. Este reflejo controla cómo nuestro sentido del equilibrio y el movimiento de la cabeza (nuestro sentido ‘vestibular’) dirige el movimiento de nuestros ojos (el componente ‘ocular’ se refiere a los músculos del ojo).

Por ejemplo, si miramos algo como la barra espaciadora de nuestro teclado y movemos la cabeza lentamente hacia adelante y hacia atrás, nuestros ojos generalmente pueden permanecer fijos en la barra espaciadora sin mucho esfuerzo consciente. Esto ocurre debido a la comunicación constante entre nuestro oído interno y los músculos de nuestros ojos mientras nuestra cabeza se mueve en el espacio.

Para ser un poco más técnico sobre cómo funciona esto, tenemos órganos sensoriales especiales llamados » canales semicirculares » en el oído interno que sirven como un giroscopio biológico. A medida que gira la cabeza en una dirección determinada, el fluido en estos canales cambia en relación con su movimiento. El desplazamiento de este fluido activa neuronas especializadas que a su vez activan otras neuronas para obtener la información de cómo se está girando desde el oído, al cerebelo, a los músculos que controlan el ojo. Sin embargo, hay circunstancias en las que esta línea de comunicación puede verse abrumada o interrumpida. Esta interrupción hace que nuestros ojos se muevan a pesar de que nuestras cabezas están quietas. Cuando esto sucede, tenemos nistagmus.

Por ejemplo, aquí hay un video de alguien que experimenta el reflejo vestíbulo-ocular mientras gira en una silla y nistagmus después de girar en una silla . En este caso, el nistagmus ocurre cuando la persona deja de dar vueltas en la silla porque el líquido en el oído interno continúa moviéndose por un corto tiempo a pesar de que la cabeza se ha detenido.

women is looking into the camera, her eyes show shee is looking to the side.
El nistagmus es un término que se refiere al movimiento incontrolable del ojo. Foto utilizada bajo licencia por Wanchana Olena Yakobchuk/Shutterstock.com.

La ataxia, la pérdida del movimiento coordinado, es causada por la degeneración del cerebelo. Una de las funciones principales del cerebelo es como centro de integración de cómo usamos la información sensorial entrante (tacto, vista, equilibrio, etc.) para dirigir cómo nos movemos en el espacio. Por lo tanto, vemos que a medida que la ataxia empeora, los movimientos voluntarios complejos como caminar se vuelven más difíciles de controlar. Esto también puede alterar el funcionamiento de los reflejos que utilizan el equilibrio y el movimiento de la cabeza, como el reflejo vestíbulo-ocular. A medida que se mueve la cabeza, la información sobre cómo se mueve la cabeza va inicialmente a un área específica del cerebelo que luego le dice a los músculos oculares cómo moverse.

Cuando las células cerebelosas de Purkinje de esa zona dejan de funcionar correctamente, este canal de comunicación se vuelve hiperactivo. Los músculos del ojo comienzan a moverse esporádicamente como si la cabeza se estuviera moviendo o girando, aunque estuviera quieta. Este es un síntoma importante a tratar en pacientes con ataxia. El nistagmus altera la vista y está relacionado con síntomas secundarios como mareos y náuseas. Esta combinación de síntomas obstaculiza gravemente la independencia de una persona y reduce su calidad de vida.

Si desea obtener más información sobre el nistagmus, consulte estos recursos de Johns Hopkins y la Academia Estadounidense de Oftalmología .

Escrito por Carrie Sheeler y editada por el Dr. Siddharth Nath. Publicado inicialmente en el 10 de diciembre de 2021. Traducción al español fueron hechas por FEDAES

Snapshot: What is Nystagmus?

Nystagmus, also known as ocular ataxia, is a term that refers to uncontrollable eye movement- usually a repetitive cycle of slow movement in a specific direction followed by a quick adjustment back to center. The root of this movement lies in a normal reflex that we use every day: the vestibulo-ocular reflex. This reflex controls how our sense of balance and head movement (our ‘vestibular’ sense) directs the movement of our eyes (the ‘ocular’ component refers to the eye muscles).

For example, if we look at something like the space bar on our keyboard and move our head slowly back and forth, our eyes are usually able to remain fixed on the space bar without much conscious effort. This is occurring because of constant communication between our inner ear and our eye muscles as our head is moving in space.

To get slightly more technical about how this works, we have special sensory organs called “semicircular canals” in the inner ear which serve as a biological gyroscope. As you turn your head in a given direction, fluid in these canals shifts in relation to your movement. The shifting of this fluid activates specialized neurons that in turn activate other neurons to get the information of how you are turning from the ear, to the cerebellum, to the muscles that control the eye. However, there are circumstances where this line of communication may become overwhelmed or disrupted. This disruption causes our eyes to move even though our heads are still. When this happens, we get nystagmus.

For example, here is a video of someone experiencing the vestibulo-ocular reflex while spinning in a chair and nystagmus after spinning in a chair. In this instance, nystagmus happens when the person stops spinning in the chair because the fluid in the inner ear continues moving for a short time even though the head has stopped.

women is looking into the camera, her eyes show shee is looking to the side.
As seen in the video, nystagmus can cause uncontrollable eye movement after head movement has already stopped. Photo used under license by Olena Yakobchuk/Shutterstock.com.

Ataxia, the loss of coordinated movement, is caused by degeneration of the cerebellum. One of the main roles of the cerebellum is as an integration center for how we use incoming sensory information (touch, sight, balance, etc.) to direct how we move in space. Thus, we see that as ataxia worsens, complex voluntary movements like walking become harder to control. This can also disrupt how reflexes using balance and head movement, like the vestibulo-ocular reflex, work. As one’s head moves, the information on how the head is moving initially goes to a specific area of the cerebellum which then tells the eye muscles how to move.

When the cerebellar Purkinje cells of that area stop working properly, this channel of communication becomes overactive. The eye muscles begin to move sporadically as though the head was moving or swivelling even though it is staying still. This is an important symptom to address in patients with ataxia. Nystagmus disrupts sight and is tied to secondary symptoms such as dizziness and nausea. This combination of symptoms severely impedes a person’s independence and reduces their quality of life.

If you would like to learn more about nystagmus, take a look at these resources by Johns Hopkins and the American Academy of Ophthalmology.

Snapshot written by Carrie Sheeler and edited by Dr. Siddharth Nath.

Snapshot: What is Transcranial Direct Current Stimulation (tDCS)?

Transcranial Direct Current Stimulation (tDCS) is a non-invasive method of brain stimulation. It promotes or inhibits activities in specific parts of the brain. tDCS is an experimental treatment that has been shown to result in changes in motor, cognitive and behavioural activities. It may be a valuable tool for the treatment of neurological disorders including cerebellar ataxia.

How it works

Neurons communicate with each other is through an electrical event called the action potential. The cell membrane of neurons can create differences in the concentration of charged molecules, called ions, inside and outside the cell. This separation of ions creates a voltage called the membrane potential. When a signal needs to be transduced to other neurons, a series of voltage changes in the membrane potential called the action potential occurs. The action potential propagates along the arms of the neuron, like sending a message through the cell. Once the message reaches the end of the arm where it meets up with other neurons, the initial neuron releases its neurotransmitters that deliver the message to the next neuron. And thus, the cycle continues!

tDCS works by stimulating the neurons with a weak electrical current, through electrodes placed on the scalp of the patient. These electrodes can slightly increase or decrease the resting membrane potential. This process can make it easier or harder for an action potential to occur. This either promotes or inhibits activities in specific brain regions.

Artist's depiction fo the human brain. Electrical energy is swirling around it.
tDCS is a non-invasive method of brain stimulation that promotes or inhibits activities in specific parts of the brain. Photo used under license by Andrus Ciprian/Shutterstock.com.

Application in ataxia

Due to the ability of tDCS to reversibly modulate brain activity, clinical trials have been conducted in many neurological and psychiatric disorders. Notably, a randomized, double-blind trial in 61 patients with multiple subtypes of ataxia came to completion in March 2021. After treatment with tDCS, a significant improvement in both the motor and cognitive symptoms of ataxia was observed. Patients also self-reported improvement in quality of life. The clinical assessment for motor functions was done through the scale for the assessment and rating of ataxia and the international cooperative ataxia rating scale. Assessment for cognitive functions was done through the cerebellar cognitive affective syndrome scale.

The study found that patients who went through two repeated treatment sessions with ten weeks in between had significantly better improvement when compared to patients who went through only one session of treatment. Also, the improvements persisted on average 3 to 6 months post-treatment. This means that the benefits of tDCS might last longer than previously thought.

Risks and benefits

TDCS is considered non-invasive and since its initial application in 1998, no serious or ongoing side effects have been reported. Studies have also shown that the electrical current will not interfere with vital functions of the heart and the brain stem. However, tDCS is still in its infancy. More research needs to be conducted to improve our understanding of potential risks and benefits. Temporary side effects including a mild burning/itching sensation at the stimulation sites, headache, and moderate fatigue were reported in around 17% of the patients. On the flip side, the technique uses equipment that is available on the market for other medical purposes. This makes the procedure relatively inexpensive, easily administered, and using easily replaceable equipment. TDCS could also be used in combination with other treatment methods. However, more research on combination treatments needs to be conducted to test safety and effectiveness.

If you would like to learn more about Transcranial Direct Current Stimulation, take a look at these resources by Johns Hopkins Medicine and Neuromodec.

Snapshot written by Christina (Yi) Peng and edited by Dr. David Bushart.

Spotlight: The CMRR Ataxia Imaging Team

Location: University of Minnesota, MN, USA

Year Research Group Founded:  2008

What models and techniques do you use?

A photo of the CMRR Ataxia Imaging Team
A photo of the CMRR Ataxia Imaging Team in 2019. Front row, left to right – Diane Hutter, Christophe Lenglet (PI), Gulin Oz (PI), Katie Gundry, Jayashree Chandrasekaran Back row, left to right: Brian Hanna, James Joers, Pramod Pisharady, Kathryn France, Pierre-Gilles Henry (PI), Dinesh Deelchand, Young Woo Park, Isaac Adanyeguh (insert)

Research Group Focus

What shared research questions is your group investigating?

We use high field, multi-nuclear magnetic resonance imaging (MRI) and spectroscopy (MRS) to explore how diseases impact the central nervous system. These changes can be structural, functional, biochemical and metabolic alterations. For example, we apply advanced MRI and MRS methods in neurodegenerative diseases and diabetes.

We also lead efforts in research taking place at multiple different cities across the United States and the world. As you can imagine, studies spread out across such a big area require a lot of coordination and standardization. We design robust MRI and MRS methods to be used in clinical settings like these.

Another important question for our team is how early microstructural, chemical and functional changes can be detected in the brain and spinal cord by these advanced MR methods. We are interested in looking at these changes across all stages of disease.

Why does your group do this research?

The methods we use (MRI and MRS) can provide very helpful information to be used in clinical trials. These biomarkers we look at can provide quantitative information about how a disease is progressing or changing.

There is good evidence that subtle changes in the brain can be detected by these advanced MR technologies even before patients start having symptoms. If we better understand the earliest changes that are happening in the brain, this can in turn enable interventions at a very early stage. For example, we could treat people even before brain degeneration starts to take place.

Why did you form a research group connecting multiple labs?

We came together to form the CMRR Ataxia Imaging Team to benefit from our shared and complementary expertise, experience, and personnel. We can do more together than we could apart.

Are you recruiting human participants for research?

Yes, we are! We are looking for participants for multiple different studies. You can learn more about the research we are recruiting for at the following links: READISCA,  TRACK-FA, NAF Studies, and FARA Studies. More information is also available through the UMN Ataxia Center.

A photo of the CMRR Ataxia Imaging Team in 2016
A photo of the CMRR Ataxia Imaging Team in 2016, in front of the historic 4T scanner where the first functional MR images were obtained, in CMRR courtyard. Left to right – Christophe Lenglet (PI), Sarah Larson, Gulin Oz (PI), Dinesh Deelchand, Pierre-Gilles Henry (PI), James Joers, Diane Hutter

What Labs Make Up the CMRR Ataxia Imaging Team?

The Oz Lab

Principal Investigator:  Dr. Gulin Oz

Year Founded:  2006

Our focus is on MR spectroscopy, specifically neurochemistry and metabolism studies. We focus on spinocerebellar ataxias. Also, we have been leading MRS technology harmonization across different sites and vendors.

The Henry Lab

Principal Investigator: Dr. Pierre-Gilles Henry

Year Founded:  2006

We develop advanced methods for MR spectroscopy and motion correction. Then apply these new methods to the study of biochemistry and metabolism in the brain and spinal cord in various diseases. We have been working on ataxias since 2014.

Fun Fact about the Henry Lab: The French language can often be heard in discussions in our lab!

The Lenglet Lab

Principal Investigator:  Dr. Christophe Lenglet

Year Founded:  2011

We develop mathematical and computational strategies for human brain and spinal cord connectivity mapping. We do this using high field MRI. Our research aims at better understanding the central nervous system anatomical and functional connectivity. We are especially interested in looking at this in the context of neurological and neurodegenerative diseases.

Fun Fact

Members of our team have their roots in 7 countries (US, Turkey, France, India, Mauritius, South Korea, Ghana) and 4 continents (North America, Europe, Asia, Africa)

For More Information, check out the Center for Magnetic Resonance Research (CMRR) Website!


Written by Dr. Gulin Oz, Dr. Pierre-Gilles Henry, and Dr. Christophe Lenglet, Edited by Celeste Suart