Proteins are building blocks of our bodies and some proteins play critical roles in brain development and function. Some proteins execute their functions by interacting with other proteins. In this study, the authors focused on two proteins, ataxin-1 (ATXN1) and capicua (CIC), which form a complex with each other. Previous studies have established that some genetic mutations allow for a “gain-of-function” mechanism in proteins which can cause neurodegenerative conditions. An example of this is spinocerebellar ataxia type 1 (SCA1), an adult-onset brain disease causing degenerative changes in parts of the brain related to the control of movement. SCA1 results from genetic mutations that increase the function of the ATXN1-CIC protein complex. Alternatively, genetic mutations can also result in a “loss-of-function”, producing different outcomes such as a complete loss of the protein altogether, a “shortened” dysfunctional version of the protein, or a partial loss of the protein where only 50% of the protein is made. This article details what happens when the ATXN1-CIC complex is “lost,” and what the consequences are in the developing brain.

ATXN1 and CIC play a critical role in normal brain development. The authors showed this by confirming the existence of the ATXN1-CIC complex within the developing mouse brain. Researchers then removed the ATXN1-CIC complex from the developing mouse brain and observed the effects on brain development due to the loss of this protein complex.

Multiple defects were observed in the developing brain in the absence of ATXN1-CIC. Without ATXN1-CIC, researchers reported shrinkage of the cortex (a brain region crucial for attention-span, thinking, and memory), which occurred due to a loss of neurons in that brain region. Examining the type(s) of neurons that were lost due to the missing ATXN1-CIC complex revealed that neuronal loss was only detected in a specific region of the cortex. This finding revealed that the ATXN1-CIC complex is essential for the survival of these neurons.

A number of behavioural tests were carried out by the researchers to examine the mice lacking ATXN1-CIC for altered cognitive and social skills. These tests revealed that without ATXN1-CIC in the brain, the mice exhibited hyperactivity and reduced anxiety. Additionally, these mice behaved worse in behavioural assays that tested for spatial context, indication learning and memory impairments. Furthermore, behavioural tests showed that mice lacking ATXN1-CIC in the brain demonstrated more aggressive behaviours compared to their normal counterparts. Mice also exhibited social interaction deficits that resembled traits of autism. These behavioural studies in mice highlight the significance of the CIC protein in affecting neurobehaviours.

To translate the knowledge from mice to humans, the researchers sought out patients that had mutations in the CIC gene to screen for brain developmental deficits. Through analysis of DNA sequencing, the authors found five individuals with mutations in the CIC gene. They found that patients with these genetic mutations had various neurodevelopmental deficits including intellectual disability/developmental delay, autism, attention deficit/hyperactivity disorder (ADHD), and seizures. Further analysis revealed that their mutations prevented 50% of the CIC protein from being made. Consequently this loss of functional CIC protein in the brain results in disruption of the ATXN-CIC complex formation and function, as well as abnormal brain development and neurological symptoms.

In conclusion, while the ATXN1-CIC complex is a critical player in the adult-onset brain disease spinocerebellar ataxia-1, this study demonstrates that this complex is also required for proper brain development. The findings in this study open the door for further exploration of the intricacies of neurodevelopment and developmental brain disorders. Furthermore, this study reveals the usefulness of animal models in understanding human brain development and even predicting human diseases.

Reference:

Lu, H. C. et al. Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nature Genetics 49, 527-536, doi:10.1038/ng.3808 (2017). Link to the full text article.