Comprehensive identification of the metastable subproteome dysregulated in polyglutamine spinocerebellar ataxias

Spinocerebellar ataxias (SCAs) are age-related neurodegenerative disorders clinically characterized by motor incoordination that can affect gaze, speech, gait and balance. The most prevalent SCAs, including SCA1, SCA2, SCA3, SCA6 and SCA7, are caused by abnormal expansion of a glutamine(Q)-encoding CAG repeat in the disease-causing gene. As a protein must form its correct shape to perform its function, the polyQ expansion often leads to misfolding and aggregation and is associated with the early onset and disease severity of SCAs. Distinct mechanisms have been proposed for the toxicity of disease proteins. However, it is still unknown how the expression of a single polyQ-expanded protein has such broad effects. Moreover, as aging is a risk factor for SCAs, it remains unexplored whether polyQ has a synergistic effect with aging to cause SCAs. To answer these questions, we need to understand how proteins keep their shapes. The safeguards to keep protein shapes is collectively called protein quality control machinery. The capacity of the quality control machinery declines in aging. Therefore, many proteins that heavily rely on the machinery would not keep their correct shapes and would lose their function during aging. Importantly, as polyQ is highly prone to misfolding and aggregation, it would overburden the protein quality control machinery. This would leave other proteins at risk for losing their correct shapes. To prove this assumption, I work at the intersection of SCAs and big data. I have utilized the nematode Caenorhabditis elegans (C. elegans) model of polyQ SCAs. To detect the changes in protein shapes between the mutant and normal worms, I have developed a high throughput approach that allows us to look at around 8000 proteins at a time with high precision. This advanced technology will allow us to identify those proteins that are particularly vulnerable to misfolding and aggregation in aging and in polyQ expressing animals. These proteins could