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New stem cell model for SCA1

Written by Jamie Hyde
Edited by Marija Cvetanovic, PhD

“A new matched stem cell model gives SCA1 researchers a clearer way to study disease mechanisms and test potential treatments.”

Using human stem cells to model SCA1

Without the right comparison, even the best disease model can give unclear answers.

Spinocerebellar ataxia type one (SCA1) is a rare inherited brain disease that mainly affects movement, balance and coordination. It is caused by a mutation in the ATXN1 gene. This mutation leads to the production of an abnormal form of the ATXN1 protein, which gradually damages certain brain cells over time. Because there is currently no cure for SCA1, researchers need reliable models to understand how the mutation causes disease and to test possible treatments.

This is not easy. The most affected brain cells in SCA1 cannot be directly studied in living people at the early stages of disease. Animal models, particularly mice, can help address some of these issues. However, SCA1 is exclusively a human genetic disease, so animal models must be altered to carry a disease-like mutation, and often fail to capture every feature of the human condition.

Stem cells can help bridge this gap. Stem cells are cells that can make more copies of themselves, and under the right conditions, develop into specialised cell types. Induced pluripotent stem cells (iPSCs) are human cells, often skin or blood, that have been “reprogrammed” in the laboratory so they behave like early stem cells. This allows researchers to guide iPSCs to become many different cell types, including brain cells. For SCA1, this means researchers can grow human cells containing the disease mutation in a dish, follow early disease-related changes, and test whether possible treatments can correct them.

Genetically matched controls allow for better comparison

However, a useful disease model also requires useful control. Previous SCA1 stem cell studies have compared cells from people with SCA1 to cells from unaffected relatives or unrelated healthy donors. These comparisons are valuable, but they are not perfect. Every person, even siblings (except for identical twins), carry many genetic differences between one another. This can then make it challenging to know whether differences seen in the lab are caused by the SCA1 mutation, or because of other “background” genetic differences.

This is why the new, isogenic SCA1 iPSC model generated by Laurie Kerkhof and colleagues in the Netherlands is so valuable. “Isogenic” means that the only genetic difference between the SCA1 cells and the healthy control is the SCA1 mutation. In other words, there are no longer any background genetic differences, so researchers can be more confident that any variation between the SCA1 and control iPSCs are because of the SCA1 mutation.

Using gene editing to create SCA1 stem cells

To generate the isogenic SCA1 stem cell model, the team started with a control iPSC line that contained two healthy copies of the SCA1 gene (also called ATXN1). They then used a gene editing technology, called CRISPR-Cas9, to replace one of the healthy copies with an SCA1 mutation. After editing, the cell line contained 29 repeats on one copy of the ATXN1 gene (healthy) and 54 repeats on the other (disease). This reflects the mutations seen in SCA1 patients, making it a genetically relevant, human model for disease.

Genetically matched SCA1 model passes quality control checks

After making the edited line, the researchers then checked that it still behaved like a useful stem cell model. This is important, as gene editing can stress cells, lead to off-target mutations and disrupt their behaviour. To assess the quality of their new model, the team performed several tests.

First, the researchers showed that the cells still had markers of “pluripotency”. Put simply, this means the iPSCs were still able to turn into many different cell types. This includes brain cells, which is critical for a SCA1 model. Through DNA sequencing, the researchers were able to confirm no undesired mutations had been introduced, and the only difference was the SCA1 mutation. Collectively, these quality control checks ensure that the new line is suitable for future experiments investigating SCA1.

Future Directions

The new model generated in this paper fits into a growing field of SCA1 research using human iPSCs. Previous iPSC research has already provided valuable insight into SCA1. For example, SCA1 iPSCs have shown disease-related features, including altered energy use, build-up of toxic proteins, and irregular electrical activity. Similar findings have been identified in patient tissue and highlights how iPSC models can capture important parts of SCA1 biology.

Here, the isogenic model strengthens this work by giving researchers more precise control. The model can be used to revisit and confirm some of these earlier findings. Moreover, it may also help to uncover earlier or subtler disease processes that are harder to identify when comparing genetically different people. In the longer term, this kind of model can also be used for testing potential therapeutics in a human-relevant model.

Ultimately, good models and controls are the tools that make better research possible. By creating a matched human stem cell model of SCA1, the researchers have provided the field with a more precise way to study what the SCA1 mutation does, why it effects certain brain cells, and provide a tool for testing potential therapies.

Key Words

Pluripotency: The ability of a cell to turn into all the different cell types that make up the human body

Isogenic: Genetically identical (and in cell culture, genetically identical except for the mutation you are researching)

CRISPR-Cas9: A gene editing technology that uses a “guide” to target an enzyme (like molecular scissors) to a specific region of DNA to make changes to the DNA sequence

Conflict of Interest Statement

The author, Jamie Hyde, is from the same laboratory group as several authors of the scientific article. Jamie did not work on this specific project.

Citation of Article Reviewed

Kerkhof, L. M. C., Pepers, B. A., van der Graaf, L. M., Santiago-Aranda, A., Voesenek, B. J. B., Reits, E. A. J., Buijsen, R. A. M., & van Roon-Mom, W. M. C. (2026). Generation of an isogenic human induced pluripotent stem cell line for spinocerebellar ataxia type 1. Stem cell research, 94, 103987. Advance online publication. https://doi.org/10.1016/j.scr.2026.103987