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Decreasing ATXN3 levels can alleviate some symptoms in an SCA3 mouse model

Written by Dr. Terri M Driessen  Edited by Dr. W.M.C. van Roon-Mom

Antisense oligonucleotides: a potential treatment for SCA3 that partially rescues SCA3 disease mouse models

Identifying new ways to slow down or delay neurodegenerative diseases has been a key research focus in the SCA field. There are many avenues that scientists can take to address this question. One method is to target the disease-causing protein: by lowering the levels of the disease-causing protein, scientists may be able to alter disease progression. These methods have recently been used in studies in other neurodegenerative disorders, like SCA2, Amyotrophic Lateral Sclerosis (ALS), and Huntington’s disease.

Prior work by the laboratory of Hank Paulson at the University of Michigan has suggested these methods may also work in SCA3. They used antisense oligonucleotides (ASOs) to lower the SCA3 disease-causing protein. ASOs are short DNA sequences that bind to specific pieces of RNA. When the ASOs bind to RNA, it is broken down and no protein is made. The Paulson laboratory designed ASOs that bind to ATXN3, which is the RNA associated with SCA3. These ASOs were able to lower the expression of mutant ATXN3 (Moore, et al. 2017). Importantly, they were capable of lowering the expression of mutant ATXN3 in both mouse models of SCA3 and SCA3 patient fibroblasts (Moore, et al. 2017). By removing the SCA3-causing protein from cells, they predicted that the cells would have a better chance at surviving.

This previous work was promising, but several questions remained. How long would one ASO treatment work? Would the ASO work even after the SCA3 mice started showing symptoms? Are there any obvious side effects, like increased inflammation, after ASO injection? And importantly, would lowering ATXN3 levels help with motor coordination problems in SCA3 mice?

Image of a mouse in a laboratory environment. Photo by Pixabay on

These questions were put to the test by McLoughlin and colleagues at the University of Michigan in a recent report. They first began by selecting the best ASO candidate, and set out to determine how long an injection of the ASO worked in SCA3 mice. They delivered the ASO into fluid-filled cavities of the mouse brain called ventricles. The fluid in these ventricles is cerebrospinal fluid, which helps provide the brain with nutrients. As it flows, cerebrospinal fluid can also help move ASOs to different parts of the brain. They found that the ASO lowered ATXN3 levels for 12-16 weeks after one treatment. This is consistent with other ASOs, which can typically work for months after the first treatment. Importantly, the ATXN3 decrease occurred in multiple parts of the brain that are affected in SCA3. This shows that ASO injection into the ventricles helped distribute the ASO throughout the brain.

One difficulty of ASOs is that they can sometimes trigger immune responses. This means that parts of the brain are not handling the ASO injection well, and are adversely responding to the treatment. Neurons are the major cell type in the brain, and are responsible for signaling and making connections throughout the brain. However, there are also many support cells that are equally important because they make sure that the neurons can function properly. There are two main support cells that are important in this immune response: astrocytes and microglia. Though they have slightly different functions, astrocytes and microglia can both respond when neurons are stressed. McLoughlin and colleagues looked at these cells in SCA3 mice treated with ASOs. They found that the ASO treatment did not cause a major change in these support cells, which suggests that the SCA3 mice were capable of handling the ASO treatment without a significant immune response. In fact, McLoughlin and colleagues found that the ASO treatment may actually help another type of support cell that has recently been studied in SCA3 (Ramani, et al. 2017). These cells are called oligodendrocytes, and their main function is to add a layer of insulation around the long processes of neurons. This insulation is called myelin. Just like the rubber insulation around an electrical wire, myelin helps neurons communicate with each other over long distances. The ASO treatment was actually able to partially rescue some of the changes found in SCA3 oligodendrocytes.

One of the final questions that McLoughlin and colleagues sought to answer was whether ASOs could help alleviate some of the motor coordination problems found in SCA3 mice. There are many ways to test motor coordination in mice. McLoughlin and her team used two of the most commonly used motor coordination tests: locomotor activity and beam walking. The locomotor activity test measures how much the mice walk around during a certain amount of time. In the beam walking test, mice are placed on a thin rod that they then walk across. Beam walking can be thought of like a balance beam: there is a certain amount of coordination, dexterity, and motor control required to successfully cross the beam. SCA3 mice normally have low levels of locomotor activity and take longer to finish beam walking, but with ASO treatment, SCA3 mice performed better in both tasks.

ASOs are just beginning to be approved by the Food and Drug Administration as treatments for other diseases. The first antisense oligonucleotide drug was approved for use in 2016, and works for spinal muscular atrophy (SMA), a disease that primarily affects infants and toddlers. There are also clinical trials underway for antisense-mediated therapies for ALS and Huntington’s disease. Though more work needs to be done, the results of McLoughlin and colleagues highlight a potential avenue for ASO therapy in the treatment of SCA3.

Key Terms

Spinocerebellar ataxia type 3 (SCA3): A dominantly-inherited neurodegenerative disease caused by the expansion of CAG repeats in the gene ATXN3.

 Patient fibroblasts: Fibroblasts are connective tissue cells. These cells can be taken from patients with diseases (usually by a cheek swab or small skin biopsy) and cultured in the laboratory. This allows researchers to study the disease in a human context, and to see how the cells respond to different therapeutics. The benefit of using human fibroblasts is that scientists can study the disease in human cells, which can sometimes respond differently than mouse cells to different diseases. Working with mouse models is advantageous because it lets researchers see how a disease can affect the brain when all cell-types are working together, which is something that can’t be done with human fibroblasts. Using mouse models of disease and human fibroblasts together can address these potential problems.

Immune Response: The immune system works to detect any invading pathogen or nucleic acid. While there is a lot of research on how the immune system works, researchers still do not know why some ASOs trigger an immune response, and what the mechanism is that causes an ASO-mediated immune response.

Conflict of Interest Statement

Dr. Hayley McLoughlin, who completed the research described in the summary, is a contributor to SCAsource. Dr. Terri Driessen, who wrote the research summary, and Dr. W.M.C. van Roon-Mom, who edited the summary, have no conflicts of interests to declare.

Citation of Article Reviewed

Hayley McLoughlin, Lauren R. Moore, Ravi Chopra, Robert Komlo, Megan McKenzie, Kate G. Blumenstein, Hien Zhao, Holly B. Kordasiewicz, Vikram G. Shakkottai, Henry L. Paulson. Oligonucleotide therapy mitigates disease in spinocerebellar ataxia type 3 mice. Annals of Neurology, 2018. 84:64-77. (

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