Spinocerebellar ataxia type 1 (SCA1) is a brain disease characterized by the death of neurons in the cerebellum, a brain region involved in coordinating our movements. SCA1 results from genetic mutations that cause a “gain” of function; these mutations allow the production of a dysfunctional ataxin-1 (ATXN1) protein, which is toxic to the brain cells that control the balance of our body.

ATXN1 has previously been discovered to interact and form complexes with other proteins to perform its functions; however, it was unknown if mutant ATXN1 also acted through these protein complexes to cause the brain damage associated with SCA1. Therefore, researchers looked for ATXN1 protein interactors, and found the majority of the ATXN1 protein in a complex with another protein called capicua (CIC). Additionally, the researchers noted that both ATXN1 and CIC are abundant in Purkinje cells (a type of brain cells in the cerebellum which coordinates physical movements and is vulnerable to cell death in SCA1).

Previous studies have shown that the mutant ATXN1 protein can be chemically altered to suppress neurotoxicity in SCA1. Upon discovering the ATXN1-CIC complex, the researchers investigated the effects of this chemically altered “dysfunctional” ATXN1 and found that this version of the ATXN1 protein could not stably form a complex with CIC, thereby impairing CIC function. This further emphasizes that the toxic effect of mutant ATXN1 is mediated through the ATXN1-CIC interaction.

The authors then experimented using fruit flies to determine whether CIC affects ATXN1 function, and vice versa. SCA1 in fruit flies results in physical defects in the eyes and abnormalities in wings. The researchers discovered that by ramping up the levels of CIC in fruit flies, they could ameliorate SCA1 disease phenotypes of the eyes and wings. This revealed that mutant ATXN1 disrupts CIC function to cause SCA1 pathology.

In fruit flies, altering the levels of CIC is able to modulate the toxicity of ATXN1 and mitigate some of the effects of SCA1. Another study expands on this through investigation of the effects of CIC protein levels on SCA1 in mice.

The authors genetically engineered mice to lack about 35 to 45% of their CIC proteins and produce the “toxic” ATXN1 protein causing SCA1. These mice survived longer than mice that had normal levels of CIC and SCA1. Reduced levels of CIC resulted in improved learning and memory, and milder neurodegeneration, as fewer brain cells died. The loss of CIC also improved other symptoms related to SCA1. For example, rapid weight loss is evident in SCA1 mice, but with the loss of CIC, this weight loss was prevented in the context of SCA1.

CIC levels can be influenced by some growth factors, which are proteins that promote cell growth and normally produced during physical exercise. The researchers therefore asked whether exercise would affect SCA1 disease progression. They implemented a mild exercise regimen in mice with SCA1. They placed mice on a moving wheel at a fixed speed for ten minutes at five times a week for one month, and found improvements in survival and motor coordination with exercised mice that had SCA1 in comparison to sedentary mice with SCA1. Those exercised mice with SCA1 had increased levels of a growth factor, which led to decreased levels of CIC. The authors also mention that the effects of exercise on mice with SCA1 were long lasting, well after its discontinuation.

Overall, these two studies examine the relationship between ATXN1 and CIC in the context of a neurodegenerative disease. While SCA1 is mediated through the ATXN1-CIC protein interaction, the first study also reveals that bolstering CIC levels is able to recover the disease phenotypes in fruit fly experiments. On the other hand, the second study finds that reducing the levels of CIC dampens the toxic “gain-of-function” effect of ATXN1 in SCA1, improving the overall survival and motor coordination of SCA1 mice. Both studies highlight the potential in regulating CIC for SCA1 treatment. While the two studies seem to provide conflicting results, the discrepancy might come from the different model organisms used (fruit flies versus mice). Nevertheless, both studies pinpoint that SCA1 is caused by ATXN1 and CIC protein interaction that has gone awry. Re-establishing proper ATXN1 and CIC interaction, either through genetic manipulation of CIC levels or exercise, could be a therapeutic approach for SCA1.

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.