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”

Measuring neurodegeneration in spinocerebellar ataxias

Written by Dr Hannah K Shorrock Edited by Dr. Maria do Carmo Costa

Neurofilament light chain predicts cerebellar atrophy across multiple types of spinocerebellar ataxia

A team led by Alexandra Durr at the Paris Brain Institute identified that the levels of neurofilament light chain (NfL) protein are higher in SCA1, 2, 3, and 7 patients than in the general population. The researchers also discovered that the level of NfL can predict the clinical progression of ataxia and changes in cerebellar volume. Because of this, identifying patients’ NfL levels may help to provide clearer information on disease progression in an individualized manner. This in turn means that NfL levels may be useful in refining inclusion criteria for clinical trials.

The group enrolled a total of 62 SCA patients with 17 SCA1 patients, 13 SCA2 patients, 19 SCA3 patients, and 13 SCA7 patients alongside 19 age-matched healthy individuals (“controls”) as part of the BIOSCA study. Using an ultrasensitive single-molecule array, the group measured NfL levels from blood plasma that was collected after the participants fasted.

The researchers found that NfL levels were significantly higher in SCA expansion carriers than in control participants at the start of the study (baseline). In control individuals, the group identified a correlation between age and NfL level that was not present among SCA patients. This indicates that disease stage rather than age plays a larger role in NfL levels in SCAs.

Looking at each disease individually, the group was able to generate an optimal disease cut-off score to differentiate between control and SCA patients. By comparing the different SCAs, the research group found that SCA3 had the highest NfL levels among the SCAs studied. As such, SCA3 had the most accurate disease cut-off level with 100% sensitivity and 95% specificity of defining SCA3 patients based on NfL levels.

Artist's drawing of a group of Laboratory Scientist sturying a larger-than life human brain
A team from the Paris Brain Institute identify that SCA1, 2, 3, and 7 patients have higher levels of NfL protein than the general population. Photo used under license by ivector/Shutterstock.com.
Continue reading “Measuring neurodegeneration in spinocerebellar ataxias”

¿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 the Pole Test?

The pole test is a common and straightforward test to assess motor coordination in mice. While ataxia might be easy to see in patients, it is not always as apparent in ataxia mouse models. Therefore, this fast and simple test is important for researchers to measure disease severity. It is also important to test the effect of different treatment strategies.

Small experimental mouse is on the laboratory researcher's hand with blue gloves
 Photo used under license by unoL/Shutterstock.com.

How is the pole test performed?

At the beginning of the test, the mouse is placed facing upward on the top of a long pole. The researchers then measure the time the mouse takes to turn around and climb down to the bottom of the pole. A healthy mouse typically takes 10-20 seconds to perform the task. If the mouse struggles and takes a long time to get to the bottom, it suggests that the mouse has motor coordination deficits.

Researchers commonly use the pole test because it’s a quick way to assess coordination in mice, even before the mice show obvious ataxia symptoms. The pole test takes about 5 minutes per mouse. It is thereby much faster than other motor coordination tests, such as the rotarod test, typically performed over multiple days. Another advantage is that the pole test can be repeated on the same mice multiple times. This allows for tracking how a mouse’s motor coordination changes over time.

0 seconds - mouse is at top of a pole facing upward. 5 seconds - mouse climbs to the top of the pole to turn around, so it can face down towards the ground. 10 seconds - mouse has climbed down the pole
Cartoon of mouse performing the pole test. Time is shown in seconds. Image courtesy of Eder Xhako.

How is the pole test used in literature?

One example of the pole test being used in the literature is a study by Nitschke and colleagues. In this study, the researchers identified a small regulatory RNA, miR760, that regulates the levels of ATXN1. ATXN1 is the gene that causes Spinocerebellar Ataxia Type 1 (SCA1). The group showed that injections of miR760 in the brain decreases ATXN1 protein levels in a SCA1 mouse model. The researchers then used the pole test to measure how the treatment with miR760 would affect the ataxia phenotype in the SCA1 model. They found that one month after the treatment the mice displayed improved motor coordination compared to control mice.  

If you would like to learn more about the Pole Test, take a look at this resource by Melior Discovery. You can learn more about other motor coordination tests in our past Snapshots on the Rotarod Test.

Snapshot written by Eder Xhako and edited by Dr. Larissa Nitschke.

SCAsource Becomes a Partner of the Ataxia Global Initiative

The SCAsource team is pleased to announce that we have become a partner of the Ataxia Global Initiative (AGI)!

Megaphone with the words "Important Announcement" written in all capital letters
We have an important announcement to share with you. Photo used under license by 4zevar/Shutterstock.com.

The AGI is an international collaboration to assist the development of treatments for ataxia. Some of the work of the AGI includes promoting open data sharing and building skills to prepare for clinical trials. The AGI also has the goal of sharing information about clinical research with people with ataxia and the public.

The SCAsource team is thrilled to connect with ataxia researchers across the globe who are part of the AGI. Their diverse perspectives will help us better represent worldwide ataxia research. We are so excited to support the AGI with its goal of making ataxia research information accessible and open!

You can learn more about the Ataxia Global Initiative and its ongoing projects at its website.