Researchers at Texas Children's Duncan Neurological Research Institute and Baylor College of Medicine announced on July 20 new findings that help explain why certain brain regions are more vulnerable to damage in spinocerebellar ataxia type 1 (SCA1), despite the presence of harmful proteins throughout the brain. The study, published in Genes & Development, used animal models to show that different forms and levels of partner proteins involved in SCA1 lead to distinct molecular interactions and biological outcomes depending on the tissue.
The research suggests that targeting therapies to specific protein forms may improve treatment for SCA1 and potentially other neurological diseases. Dr. Huda Zoghbi, corresponding author and founding director of Duncan NRI, said, "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."
A mutation in the ATAXIN-1 gene causes SCA1 by producing a faulty protein that accumulates inside cells. Although this gene is expressed widely across different tissues including other parts of the body such as heart and liver, only certain areas like the cerebellum and brain stem are particularly susceptible to its effects. The team found that Capicua (CIC) is an important partner protein for ATXN1; both are present throughout the brain but drive toxicity mainly in regions affected by SCA1.
First author Hamin Lee said, "Interestingly, lacking ATXN1 does not cause ataxia but leads to learning and memory deficits... all characteristics associated with Alzheimer's disease." The researchers also examined a similar protein called ataxin-1-like (ATXN1L). Removing ATXN1L caused abnormalities including lung defects or perinatal mortality.
By genetically engineering mice lacking either CIC-S or CIC-L forms individually, they discovered non-interchangeable roles: mice without CIC-S experienced early death or developmental issues while those without CIC-L developed behavioral problems. Pairings between these proteins were also specific—CIC-L prefers binding with ATXN1 while CIC-S binds with ATXN1L—leading to distinct vulnerabilities depending on which combination was disrupted.
Zoghbi concluded, "Our findings show that subtle differences in relative abundance of CIC and ATXN1 forms at the protein level... can result in highly specialized functions and dictate regional vulnerability... Our study illuminates an improved understanding of neurological disease."
