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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El tratamiento para la SCA1 no causa efectos secundarios no deseados en un modelo de ratón

Escrito por el Dr. Ronald Buijsen Editado por la Dra. Larissa Nitschke. Publicado inicialmente en el 28 de Enero de 2021. Traducción al español fueron hechas por FEDAES y Carlos Barba.

O’Callaghan y sus colegas muestran que los enfoques terapéuticos novedosos para reducir la proteína que causa la enfermedad en SCA1 no aumentan el riesgo de desarrollar cáncer o enfermedad de Alzheimer en ratones SCA1.

Las personas afectadas con ataxia espinocerebelosa tipo 1 o SCA1 llevan una expansión de un tramo repetitiva de ADN en el ATXN1 gen. La expandido ATXN1 gen codifica una proteína expandido ataxina-1, que se acumula y causa toxicidad en el cerebro. Esto provoca problemas de coordinación motora y letalidad prematura. Hasta ahora, no existe ningún tratamiento que ralentice, detenga o revierta la progresión de la enfermedad SCA1.

Aún así, varios estudios preclínicos demostraron que la reducción de los niveles de proteína ataxina-1 puede mejorar los déficits de coordinación motora en modelos de ratón SCA1. Una estrategia para reducir los niveles de ataxina-1 es el uso de oligonucleótidos antisentido (ASO) . Estos tratamientos de ASO escinden específicamente el ARNm de Atxn1 y reducen los niveles de proteína ataxina-1.

Este estudio, publicado por el grupo del Dr. Harry Orr en 2018 , mostró que la inyección de ASO en el cerebro de ratones SCA1 mejora los déficits motores, prolonga la supervivencia y revierte las anomalías neuroquímicas. Sin embargo, la reducción de los niveles de la proteína ataxina-1 podría provocar una expresión alterada de otras proteínas en el cerebro. Esto podría afectar la seguridad de esta estrategia de tratamiento. Por lo tanto, este estudio de seguimiento investigó si la reducción de los niveles de proteína ataxina-1 produce efectos no deseados.

a brown laboratory mouse sits in a researcher's gloved hand
El tratamiento con ASO para reducir los niveles de ataxina-1 no causa efectos secundarios no deseados en un modelo de ratón SCA1. La Imagen fue obtenida de Rama de Wikimedia.
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Results of the RISCA study: gaining a better understanding of how ataxia symptoms first appear in at-risk patients

Written By Dr. David Bushart Edited by Celeste Suart

The RISCA study will help researchers design smarter, more efficient clinical trials by teaching us about the very early stages of SCA

Ataxia research has grown significantly in recent years. Although much work still remains, we are gaining a better understanding of how ataxia affects patients. Several exciting, new therapies are currently being studied. These advances would not be possible without the involvement of ataxia patients in clinical research studies. Some clinical studies are drug trials, where patients are enrolled to help researchers determine whether new therapies are effective at treating ataxia. However, other equally important types of clinical studies also exist. Ataxia patients play a critical role in the success of these studies.

What would an ideal treatment for ataxia look like? Ideally, we would be able to treat patients when their symptoms are very mild, or perhaps even before their symptoms appear at all. However, there are several obstacles to developing and testing this kind of hypothetical treatment:

First, it can be hard to know which patients to treat if symptoms are not yet present! There are many people who descend from patients affected by SCA of some kind. They have a 50% chance of being affected. While some of these people have been genetically tested, many have not. This makes it difficult to predict whether they will eventually develop SCA at all.

Second, along those lines, it could be very difficult to predict whether a drug is working to prevent symptoms from appearing if we don’t know precisely when symptoms should appear. It is much easier to tell if a drug is working when it is given to a patient with obvious symptoms – if their symptoms improve, the drug works.

Third, it can be difficult for researchers to enroll enough patients into clinical trials to get a meaningful result. This is complicated by the fact that we don’t know the answers to the first two questions above. Until recently, it remained unclear how a trial to test such a hypothetical treatment would need to be designed.

Thankfully, recent work has helped us better understand the answers to these questions. Results from the RISCA study were recently released. RISCA, which is a prospective, longitudinal, observational cohort study, was designed to study individuals who are at-risk for developing SCA, and how SCA symptoms might first appear.

Doctor and patient discussing something while sitting at the table
The RISCA study was designed to give doctors and patients more information about when ataxia symptoms first start to appear. This information is incredibly important for future ataxia clinical trials. Photo used under license by S_L/
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ASO treatment to lower ataxin-1 levels doesn’t cause unwanted side effects in a SCA1 mouse model

Written by Dr. Ronald Buijsen Edited by Dr. Larissa Nitschke

O’Callaghan and colleagues show that novel therapeutic approaches to reduce the disease-causing protein in SCA1 do not increase the risk of developing cancer or Alzheimer’s disease in SCA1 mice.

People affected with Spinocerebellar Ataxia type 1 or SCA1 carry an expansion of a repetitive stretch of DNA in the ATXN1 gene. The expanded ATXN1 gene encodes an expanded ataxin-1 protein, which accumulates and causes toxicity in the brain. This causes motor coordination problems and premature lethality. So far, there is no treatment that slows, stops, or reverses SCA1 disease progression.

Still, several preclinical studies demonstrated that reducing ataxin-1 protein levels can improve the motor coordination deficits in SCA1 mouse models. One strategy to reduce ataxin-1 levels is the use of antisense oligonucleotides (ASO). These ASO treatments specifically cleave Atxn1 mRNA and lower ataxin-1 protein levels.

This study, published by the group of Dr. Harry Orr in 2018, showed that injection of ASOs into the brain of SCA1 mice improves motor deficits, prolonged survival, and reversed neurochemical abnormalities. However, lowering ataxin-1 protein levels might lead to altered expression of other proteins in the brain. This could impact the safety of this treatment strategy. Therefore, this follow-up study investigated whether lowering of ataxin-1 protein levels results in unwanted effects.

a brown laboratory mouse sits in a researcher's gloved hand
ASO research in SCA1 is promising. But before moving forward, more safety testing had to be done in SCA1 mouse models. Image courtesy of Rama on Wikimedia.
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Levels of Capicua may make SCA1 neurodegeneration worse in parts of the brain

Written by Stephanie Coffin Edited by Dr. Brenda Toscano

Ataxin-1 may not be the only protein important in driving neurodegeneration in SCA1

Why does a protein that cause disease only cause toxicity in specific regions of the brain, despite being in all cells of the body?  This is the question authors attempt to answer in this article, with a focus on spinocerebellar ataxia type 1 (SCA1) and the disease causing protein, Ataxin-1.  SCA1 is a polyglutamine expansion disorder, meaning patients with the disease have a CAG repeat in the ATXN1 gene that is larger than that of the healthy population.  This mutant allele is then translated into a mutant protein, causing SCA1.  Ataxin-1 protein is expressed throughout the entire brain, however, toxicity (cell death and problems) is mainly restricted to neurons of the cerebellum and brainstem.  This phenomenon is called “selective vulnerability” and refers to disorders in which a restricted group of neurons degenerate, despite widespread expression of the disease protein.  Selective vulnerability occurs in many diseases, including Alzheimer’s, Huntington’s, and Parkinson’s disease and is currently under investigation by many scientists in the field of neurodegeneration.

In SCA1, this selective vulnerability can be narrowed further in the cerebellum. The cerebellum is broken down into lobules (I-X), with lobules II-V described as the anterior region and lobules IX-X as the nodular zone. Studies have previously shown cerebellar Purkinje cells to be particularly sensitive to mutant ataxin-1, and within the cerebellum, neurons in the anterior region degenerate faster than those in the nodular zone.  This paper wanted to understand the mechanism of this interesting biology, hypothesizing that there are genes whose are expressed mainly in these zones could correlate with the pattern of Purkinje cell degeneration. To this end, the authors used the mouse model ataxin-1 [82Q], which overexpresses human ataxin-1 with 82 CAG repeats specifically in cerebellar Purkinje cells.

Doctor howing up a scan of the human brain
Why do some parts of the brain degenerate in SCA1, when the disease causing protein is expressed in all pWhy do some regions of the brain degenerate in SCA1, when the disease-causing protein is expressed in all parts of the body? Why don’t other regions show the same signs of disease? This is what researchers sought to find out in this study. Photo by Anna Shvets on

First, the authors confirmed the finding that neurons from the anterior region of the cerebellum degenerate earlier than those in the nodular zone.  They did this by assessing the health and number of Purkinje cells, which indeed appeared to be better in the cells located in the nodular zone.  Next, techniques assessing expression of RNA in SCA1 and control cerebellum, showed that there are a number of genes which are uniquely dysregulated in the anterior cerebellum of SCA1 mice.  Neurons function and communicate with each other via ion channels, and interestingly, the genes found to be dysregulated in the anterior cerebellum of SCA1 mice were related to ion channel signaling.

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