Grant: Project Grant

Spinocerebellar ataxia type 6 (SCA6) is a devastating genetic disease that leads to progressive motor impairment (called ataxia) and cerebellar degeneration. SCA6 currently has no known treatment. Using a mouse model of SCA6, we identified cellular changes in the cerebellum that we believe contribute to the disease, since rescuing these cellular changes led to reduced ataxia. We identified two promising treatment strategies that reduced ataxia: (1) an FDA-approved drug called 4-AP and (2) a behavioural intervention, exercise. Our results show that these two interventions improve cellular function in the SCA6 mouse cerebellum, but in different manners. However, a detailed understanding of their action is presently unknown. Here, we aim to unravel the mechanisms that underlie the improvements in ataxia in SCA6 mice caused by 4-AP and exercise, in the hope that this may lead to new, more specific treatment avenues in the future. We will furthermore test whether 4-AP and exercise can work synergistically to improve ataxia in SCA6 mice, which is likely given their different effects. This work will result in important findings that could directly contribute to new treatments for a currently untreatable disease. Furthermore, since several other forms of ataxia, as well as aging, have common changes in the cerebellum, our findings may have broader impact on other degenerative diseases as well.