Reduced activity of Purkinje cells appears early in ARSACS and may be an important driver of cerebellar dysfunction and ataxia. Previous research showed that treating ARSACS mice with the mitochondria-targeted antioxidant MitoQ did not correct these firing abnormalities, suggesting that mitochondrial dysfunction alone does not explain the problem. Dr. Maltecca’s team has identified an abnormal accumulation of Cav2.1 calcium channels at the membrane of Purkinje cells, leading to excessive calcium entry and overactivation of KCa2.2 channels. The researchers have also identified two new small molecules that selectively inhibit Cav2.1. This project will test whether targeting Cav2.1 can restore normal Purkinje cell activity and improve disease-related abnormalities in ARSACS models. The findings could establish Cav2.1 inhibition as a targeted therapeutic strategy for ARSACS and potentially inform research on other Cav2.1 gain-of-function disorders.
Subvention : $100 000
Durée : un an
Dre Francesca Maltecca
IRCCS Ospedale San Raffaele
Milan, Italy
Contact : maltecca.francesca@hsr.it