Spinocerebellar ataxia type 1 (SCA1) is a brain disease that causes the death of neurons in the cerebellum, the part of the brain responsible for coordinating our movements and balance. SCA1 happens because of genetic mutations that create a faulty version of a protein called ataxin-1 (ATXN1). This mutant ATXN1 protein is toxic to brain cells that control body movement.

Scientists knew that ATXN1 works by teaming up with other proteins, but it wasn’t clear whether the mutant form caused damage through these partnerships. To investigate, researchers looked for proteins that bind to ATXN1 and found that most ATXN1 proteins form a complex with another protein called capicua (CIC). Both ATXN1 and CIC are abundant in Purkinje cells—special neurons in the cerebellum that are crucial for movement and vulnerable to damage in SCA1.

Previous research showed that chemically altering mutant ATXN1 could reduce its harmful effects. The researchers found that this altered ATXN1 couldn’t form a stable complex with CIC, which impaired CIC’s function. This finding suggests that the toxic effects of mutant ATXN1 depend on its interaction with CIC.

To better understand how ATXN1 and CIC interact, the researchers turned to fruit flies, a common model for studying genetics. Fruit flies with SCA1 show physical problems like defects in their eyes and wings. Remarkably, increasing CIC levels in these flies improved their eye and wing defects. This showed that mutant ATXN1 disrupts CIC’s function and that boosting CIC can reduce the damage caused by SCA1 in fruit flies.

Another study examined the role of CIC in mice with SCA1. Scientists genetically engineered mice to produce the toxic ATXN1 protein but with reduced levels of CIC (about 35–45% less than normal). These mice lived longer and showed better learning, memory, and less brain cell death than mice with normal CIC levels. They also avoided rapid weight loss, a common symptom in SCA1 mice. This suggests that lowering CIC levels can reduce the harmful effects of mutant ATXN1 in mice.

Because CIC levels can be affected by growth factors—proteins produced during exercise that encourage cell growth—the researchers tested whether exercise might help mice with SCA1. Mice ran on a moving wheel for 10 minutes, five times a week, for one month. The exercised mice lived longer and had better motor coordination than sedentary mice. Exercise increased growth factors that lowered CIC levels, helping reduce SCA1 symptoms. Notably, these benefits lasted well after the exercise stopped.

In summary, these two studies explore the complex relationship between ATXN1 and CIC in SCA1:

In fruit flies, increasing CIC levels helped improve SCA1 symptoms.

In mice, decreasing CIC levels reduced disease severity and improved survival.

Although these findings seem contradictory, they might reflect differences between species or how the proteins work in different contexts. Both studies agree that the harmful interaction between ATXN1 and CIC plays a central role in SCA1. Finding ways to restore the proper balance of these proteins—either by adjusting CIC levels genetically or through exercise—could lead to new treatments for this movement disorder.

References:

1. Fryer J. D. et al. Exercise and genetic rescue of SCA1 via the transcriptional repressor Capicua. Science. 334, 690-693 (2011). Link to the full text article.

2. Lam, Y. C. et al. ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell. 127, 1335-1347 (2006). Link to the full text article.