Unravelling the role of NOVA splicing factors in cerebellar neurodegeneration associated to spinocerebellar ataxia type 37

Spinocerebellar Ataxia type 37 (SCA37) is a rare inherited brain disorder that mainly affects coordination, balance, and movement due to the progressive degeneration of the cerebellum, the region of the brain responsible for motor control. This disease is caused by a genetic mutation involving the repetition of a short DNA sequence (ATTTC) in a non-coding region of the DAB1 gene. Although the exact disease mechanism is still largely unknown, current evidence suggests that these repeated sequences can accumulate within cells and form abnormal RNA structures, known as RNA foci. These foci may trap specific proteins involved in RNA metabolism, a process essential for the health and survival of cells, thus disturbing normal cellular functions and leading to brain cell damage. Our preliminary findings indicate that two key proteins, NOVA1 and NOVA2, which play essential roles in brain cell development and function, interact with these toxic RNA structures. This project aims to understand how these interactions affect brain function, with a particular focus on how they disrupt RNA splicing, a process that is crucial for producing the correct proteins required by nerve cells. To address these questions, we will use a combination of experimental models, including cultured cells, cerebellar neurons, and a newly developed mouse model of the disease. The ultimate goal is to uncover the molecular mechanisms underlying SCA37 and to identify potential therapeutic targets that could pave the way for future treatments for patients affected by this debilitating condition.