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/Shutterstock.com.

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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Snapshot: What is the Morris Water Maze Test?

Spinocerebellar ataxias (SCAs) are well known for worsening motor coordination symptoms caused by the degeneration of the cerebellum. Yet, increasing reports indicate that broader changes are occurring in the brains of some SCA patients. This includes changes in the hippocampus, a brain region critical for learning and memory. One way to test learning and memory in mice is the Morris Water Maze Test. Researchers use this test on SCA mouse models to investigate how and when learning and memory symptoms arise. More importantly, we can also use this test to evaluate the effect of potential treatments on learning and memory.

white mouse swimming with its head poking up above the water
Although mice can swim quite well, they don’t like swimming. The Morris Water Maze takes advantage of this to test the learning and memory of mice. Photo used under license by Aleksandar Risteski/Shutterstock.com.

The Morris Water Maze consists of a large circular pool of opaque water. A platform is placed in the pool just under the surface of the water so that the mouse won’t be able to see it. Though mice are good swimmers, they don’t particularly enjoy swimming. Mice will always attempt to find the platform as quickly as possible. Shapes on the walls around the pool help the mice orient themselves within the pool (first panel in the figure below).

The first time a mouse swims in the pool (second panel in the figure), the mouse tends to swim aimlessly around until they eventually find the hidden platform. Each subsequent time the mouse swims in the pool, the mouse will get better and better. Using the shapes on the wall to help identify where they are in the pool, the mouse will eventually learn and memorize the platform’s location.

First day, mouse does not know wehere the plaform is an swims a lot. Second day, the mouse still swims a while but remembers where the platform is. On the last day, the mouse knows where the platform is and goes right there.
The three steps in the Morris Water Maze. Image made by Larissa Nitschke use BioRender.

As that happens, they will be better and better at the task. Eventually, the mice will swim immediately to the platform when placed in the pool (third panel in the figure). Researchers can measure this improvement by measuring how much time it takes the mouse to reach the platform and the length of its path to the platform. Additionally, to assess the strength of the memory, researchers can take out the platform from the pool in what is called a “probe trial”. Mice that spend more time in the area where the platform used to be are considered to have built the strongest memories of that location.

As is the case for some SCA mouse models, mice with impaired learning and memory have more difficulty learning and remembering the correct location of the platform. As a result, they spend a longer time searching for and swim longer distances to the platform. Overall, they display a poorer improvement over time. By using the Morris Water Maze Test on SCA models that receive different treatments, scientists can then further test which therapy could improve their learning and memory symptoms. Therefore, the Morris Water Maze Test may help identify new therapeutic strategies to treat learning and memory problems in patients.

If you would like to learn more about the Morris Water Maze, take a look at these resources by the Scholarpedia and JOVE.

Snapshot written by Carrie Sheeler and edited by Dr. Larissa Nitschke.

Snapshot: What is the balance beam test?

When you think of a balance beam, you might think of gymnastics. For humans, a balance beam is a surface where we perform jumps, flips, and other athletic feats. Whether it’s a child taking their first class, or an Olympic athlete going for gold, the balance beam requires both balance and coordination. When a scientist puts a mouse through the balance beam test, they don’t ask them to do this kind of complicated routine, but they are testing those same abilities.

Little Black Mouse on a White Background
Little Black Mouse on a White Background. Photo used under license by Michiel de Wit/Shutterstock.com.

The equipment setup for the balance beam test is simple: two platforms with a beam running between them plus lots of padding underneath so the mouse doesn’t get hurt if it falls off. Over multiple days, the scientist will train the mouse to run across the beam from one platform to another. Once the mouse has been trained, it will go through multiple official test runs. In these tests, the scientist will measure the time it takes for the mouse to cross the beam. They will also count the number of times one of its paws slips off the beam during the crossing. You can see some videos of mice doing the test here.

Mice that have problems with balance and coordination usually take longer to cross the balance beam and have more paw slips during the crossing. The mice might take longer to cross because they are clinging to the beam to try to stay on. Their paws might slip more because they cannot coordinate their movements properly. The scientist can also compare the measurements from the first day of training with the measures taken during the official runs. This shows how well the mouse learned to stay on the beam. This is useful because learning how to do a task and performing the task are two different things. Some parts of the brain are more important for learning, while others are more important for doing the task. Thus, telling those two aspects apart can be useful.

Mouse cossing a balance beam connecting two platforms

A typical balance beam setup, with two platforms and a beam between them. Image by Amy Smith-Dijak.

The balance beam test has been used to understand balance and coordination in both healthy mice and mouse models of disease. In healthy mice, scientists studying the basic biology of balance and coordination use this assay to test if changing the way particular parts of the brain work changes the mouse’s performance. For diseases in which lack of balance and coordination are major features, such as spinocerebellar ataxias, this test is a simple way to check how fast the disease progresses in mouse models. The assay can further be used to test possible treatments for these diseases: better scores after the treatment indicate that the therapy helped the mice improve their balance and coordination.

To sum it up, the balance beam test is a simple and effective assay to measure a mouse’s balance and coordination. Its use helps scientists to understand the basic biology of balance and coordination, as well as uncover why they are impaired in some diseases. Using the balance beam test on mouse models of disease that underwent different treatments, scientists can further measure if the therapy would improve the mouse’s balance and coordination. Therefore, the balance beam test might even help to find new treatments for motor coordination diseases.

If you would like to learn more about the balance beam test, take a look at these resources by the Maze Engineers and Creative Biolabs.

Snapshot written by Dr. Amy Smith-Dijak and edited by Dr.Larissa Nitschke.

Eliminación de la proteína ataxina-2 agregada como vía terapéutica para SCA2

Escrito por el Dr. Vitaliy Bondar Editado por el Dr. Hayley McLoughlin. Publicado inicialmente en el 5 de febrero de 2021. Traducción al español fueron hechas por FEDAES y Carlos Barba.

Una nueva investigación sugiere que la proteína ataxina-2 mutante abruma a las células en SCA2, lo que lleva a una disminución de la autofagia y la eliminación de las proteínas dañadas.

Se pueden hacer muchas comparaciones entre células y seres humanos. Al igual que los humanos, las células pueden acumular basura y desechos en ciertos momentos y este desorden con el tiempo se vuelve problemático e incluso tóxico. Esto es precisamente lo que Jonathan Henry Wardman y sus colegas de la Universidad de Copenhague decidieron investigar a nivel celular. Preguntaron si la falta de una eliminación adecuada de las proteínas defectuosas de la enfermedad afecta la supervivencia y el bienestar celular.

Los investigadores optaron por estudiar células derivadas de un paciente que tiene ataxia espinocerebelosa tipo 2 (SCA2). La causa de SCA2 es la expansión de la repetición CAG en el gen ATAXIN-2 , que codifica la cadena de aminoácidos de poliglutamina en una proteína de unión al ARN , ataxina-2. Se encuentra que la proteína ATXN2 expandida poliQ defectuosa se agrega dentro de la célula y las horas extraordinarias pueden afectar su supervivencia. La acumulación de productos proteicos agregados derivados de genes mutados es un sello distintivo de muchos tipos de ataxias espinocerebelosas, así como de otras formas de trastornos neurodegenerativos como la enfermedad de Parkinson.

No está claro cómo la agregación de proteínas afecta la supervivencia celular. Sin embargo, se han correlacionado múltiples defectos celulares con la agregación de ataxina-2. Por ejemplo, se ha informado que las mitocondrias que generan energía para una célula funcionan de manera anormal en modelos celulares SCA2. Además, un mecanismo de depuración celular, llamado autofagia , que es responsable de limpiar los compartimentos celulares defectuosos y ciertas proteínas rotas, se muestra menos eficaz en varios modelos de SCA2. Estos mecanismos los autores decidieron investigar en su artículo de investigación recientemente publicado.

scientist using microscope
Una nueva investigación que utiliza células SCA2 arroja luz sobre las causas de los síntomas de la enfermedad. Foto de Chokniti Khongchum en Pexels.com

Los científicos identificaron por primera vez la evidencia de disfunción celular SCA2 mediante la detección de una elevación significativa de los niveles de caspasa-9 y caspasa-8. Son proteínas que indican estrés celular y muerte. Los autores plantearon la hipótesis de que dicha disfunción celular puede deberse a la acumulación de ataxina-2 defectuosa. Para probar esta hipótesis, decidieron bloquear sistemáticamente dos vías celulares que procesan proteínas defectuosas: proteostasis y autofagia.

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Spotlight: The Movement Analysis and Robotics Laboratory (MARlab)

MAR lab logo

Principal Investigator: Dr. Maurizio Petrarca

Location: Bambino Gesù Children Hospital, Rome, Italy

Year Founded: 2000

What models and techniques do you use?

  • Wearable Technologies
  • Movement analysis
  • Robotics
  • Clinical standardized assessment tools
Seven researchers stand infrom of a presentation screen
This is group picture taken during a conference. From left to right: Silvia Minosse, Alberto Romano, Martina Favetta, Maurizio Petrarca (PI), Gessica Vasco, Susanna Summa and Riccardo Carbonetti. Image courtesy of Susanna Summa.

Research Focus

What is your research about?

MARlab has a lot of experience in the rehabilitation of children with motor disorders including cerebellar diseases. We specialize in the use of motion analysis systems and robotics. Using advanced tools, we customize assessments and rehabilitative settings matching children needs in an ecological context.

We are involved in research to define specific digital biomarker and we are exploring different technological solutions, including wearable technology, to monitor the patient at home.

Rehabilitative competencies assure clinical opportunity in developing technological tools for training and assessment of the postural control, upper-limb coordination, gait, speech and cognition in pathological conditions.

Why do you do this research?

Ataxias are rare and chronic diseases usually without cure. The progression of the disease needs to be monitored periodically, so patients visit the hospital to control their condition by performing several clinical protocols. Developing more accurate and precise technology, to measure symptoms remotely, will help us better measure the impact of different treatments and rehabilitation in ecological contexts, decreasing the patient’s stress. This will help researchers and doctors knowing what works best for the patient. 

Bambino Gesù Children Hospital Logo

The Movement Analysis and Robotics Laboratory (MARlab) is located in the Bambino Gesù Children Hospital in Rome, Italy.

Fun Fact

We are a pediatric hospital very close to sea and our walls are painted with underwater landscapes.

A hospital walkway with the walls painted with sea creatures and submarines

For More Information, check out the Bambino Gesù Children Hospital website!


Written by Dr. Susanna Summa, Edited by Celeste Suart