Study reveals why rare neurological disease damages specific brain regions

Many neurological diseases damage specific parts of the brain, even though the harmful protein involved is present throughout the brain. Researchers at Texas Children's Duncan Neurological Research Institute (Duncan NRI) and Baylor College of Medicine report in Genes & Development new evidence that explains these differences in brain tissue vulnerability.

Working with animal models of human spinocerebellar ataxia type 1 (SCA1), the team showed that different forms as well as levels of partner proteins involved in the disease can lead to distinct molecular interactions and biological outcomes in different tissues. The findings, which could be applied to other conditions, suggest that directing therapies to specific protein forms may improve treatment.

"SCA1 is a rare neurodegenerative disorder characterized by progressive loss of coordination (ataxia), slurred speech and swallowing difficulties, which result from damage to the cerebellum, the brain region that controls coordination and balance," said Dr. Huda Zoghbi, corresponding author and Duncan NRI Founding Director, who is also a Distinguished Service Professor at Baylor College of Medicine and an Investigator with the Howard Hughes Medical Institute.

A mutation in the ATAXIN-1 (ATXN1) gene causes SCA1. This mutation produces a faulty protein that is overly active and accumulates inside cells, damaging them. Although the human ATXN1 gene is expressed in many brain regions and other parts of the body such as the heart and the liver, the cerebellum and the brain stem are the most vulnerable to the harmful effects of defective ATXN1 protein.

Multiple studies in the lab have shown that Capicua (CIC) is an important partner of ATXN1, and in this new study the researchers finally provide an explanation for why CIC, which, like ATXN1, is expressed throughout the brain, drives toxicity in the cerebellum but no other tissues affected in SCA1. To answer this question, the authors went back to basics. They decided to understand the biology of these proteins and the consequences of their loss.

"Interestingly, lacking ATXN1 does not cause ataxia but leads to learning and memory deficits, and Atxn1 knock-out in mice increases amyloid beta production, all characteristics associated with Alzheimer's disease and affecting the cortex and hippocampus but not the cerebellum," said first author Hamin Lee, a graduate student in the Zoghbi lab.

In addition to ATXN1, the body produces a similar protein called ataxin-1-like (ATXN1L). Eliminating ATXN1L in animal models led to yet another set of abnormalities, including lung defects, perinatal mortality, or death of newborns shortly after the time of birth, and hydrocephalus, an abnormal buildup of cerebrospinal fluid within the brain's cavities, which can lead to brain damage.

Different tissues are affected by loss of ATXN1 and ATXN1L, which suggests that they interact with different proteins. However, previous studies had shown that they both bind to and stabilize the same protein, CIC, throughout the body. How do these two similar proteins, both associated with CIC, produce distinct outcomes?

We knew that CIC exists in two forms, CIC-Long (CIC-L) and CIC-Short (CIC-S). Both ATXN1 and ATXN1L bind to the same section on both CICs. CIC-L and CIC-S differ at one end of the protein, suggesting that the two forms play distinct biological roles."

Hamin Lee, first author

The researchers investigated the roles of the two CICs by genetically engineering mice to lack only one of the forms at a time. They found striking differences.

On one side, many mice without CIC-S died early in life and had developmental problems, especially in the lungs. Some mice also built up fluid in the brain, showed poor growth over time and eventually died. On the other side, mice without CIC-L survived but developed behavioral problems, learning and memory difficulties, movement deficits and hyperactivity. "These findings showed that the two forms of CIC are not interchangeable, each has its own essential function," Lee said.

Given the similar symptoms observed in mice lacking CIC-S and ATXN1L, and in mice lacking CIC-L and ATXN1, the team took a closer look at the interactions of the two CICs with ATXN1 and ATXN1L. They discovered that pairings were specific: CIC-L prefers to bind ATXN1 and CIC-S prefers to bind ATXN1L. Loss of ATXN1 affects CIC-L protein stability more, which may underlie their similar disease characteristics.

Furthermore, the levels of these proteins vary depending on the brain region and stage of development. For instance, the cerebellum has the highest levels of CIC and that may be especially vulnerable to overactive ATXN1, and during lung development ATXN1L is highest along with high level of CIC-S. "This means that certain areas are more vulnerable if a specific protein partnership is disrupted," Lee said.

"Our findings show that subtle differences in the relative abundance of CIC and ATXN1 forms at the protein level, together with the differential complexes they assemble, can result in highly specialized functions and dictate regional vulnerability," Zoghbi said. "Our study illuminates an improved understanding of neurological disease and offers new possibilities to comprehend and treat these conditions more effectively."

Esmeralda Villavicencio Gonzalez, Elias M. Rivera, Mark A. Durham, Ronald Richman, Elizabeth H.-Y. Chu, Kailey Xia, Hu Chen, Zhandong Liu, Surabi Veeraragavan and Binoy Shivanna, all at Baylor College of Medicine and/or Texas Children's Hospital, also contributed to this work.

This work was funded by National Institute of Aging (F31 AG077918), Cockrell Family Funding, National Institute of Neurological Disorders and Stroke (R01 NS027699), Freedom Together Foundation (MR-2023-4260), Howard Hughes Medical Institute, National Heart, Lung, and Blood Institute (R01 HL181470), Chao Endowment, Huffington Foundation, National Institutes of Health Cancer Center (P30 CA125123), Cancer Biology Research (1R50CA283804) and Eunice Kennedy Shriver National Institute of Child Health and Human Development Intellectual and Developmental Disabilities Research Center (P50HD103555).