Many diseases happen because a protein in the body isn’t working properly. Spinocerebellar ataxia type 1, or SCA1, is a disease where brain cells in the cerebellum—the part of the brain that controls our movement and balance—start to die. This leads to problems with coordination and movement.

SCA1 is caused by a mutation in a gene that makes a protein called ataxin-1 (ATXN1). This mutation causes ATXN1 to behave in an unusual way, leading to the disease.

Scientists know that ATXN1 normally teams up with another protein called capicua (CIC) to do its job. To understand how SCA1 happens, the researchers created mice with a version of ATXN1 that cannot bind to CIC. They then tested these mice to see how well they could move.

Surprisingly, mice with the disrupted ATXN1-CIC partnership showed normal movement, while mice with the usual SCA1 mutation had movement problems. When the researchers looked at the brains, they found that no brain cells died in the mice where ATXN1 and CIC couldn’t work together.

This tells us that the toxic effect of mutant ATXN1 in SCA1 depends on its interaction with CIC. The mutated ATXN1 causes the ATXN1-CIC complex to become overactive, which damages brain cells.

The researchers also studied what happens when the ATXN1-CIC complex loses its function. They found that losing the function of this complex does not cause SCA1 symptoms, showing that the disease is caused by a harmful “gain-of-function” — meaning the mutant protein does too much or acts abnormally, rather than too little.

In summary, this study shows that the harmful interaction between ATXN1 and CIC is what causes brain cell damage and movement problems in SCA1. Blocking this interaction might be a promising way to develop new treatments for this disease.

Reference:

Rousseaux M. W. et al. ATXN1-CIC complex is the primary driver of cerebellar pathology in spinocerebellar ataxia type 1 through a gain-of-function mechanism. Neuron. 97, 1235-1243 (2018). Link to the full text article.