A central theme in cerebellar ataxia is mutations in genes encoding calcium regulatory genes, highlighting the selective vulnerability of Purkinje neurons to alteration of calcium fluxes. We have recently demonstrated that the Voltage-Gated Calcium Channel (VGCC) Cav2.1 is increased in amount at the Purkinje neurons’ plasma membrane in the Sacs-/- mouse, and this results in a striking 30% augment in Cav2.1-mediated calcium currents as compared to controls. We also found that Cav2.1 overactivation is functionally connected with the reduced pacemaking firing activity of Sacs-/- Purkinje neurons. Based on these findings, the project involves a parallel screening of non-selective inhibitors already in use in the clinic to validate Cav2.1 as a target, and a de novo screening of potent and selective Cav2.1 inhibitors. The latter may represent a remarkable breakthrough due to the potential therapeutic relevance in the treatment of ARSACS and also other Cav2.1-related diseases.
Grant: $100,000
Duration : one year
Contact:
Dr. Francesca Maltecca
Ospedale San Raffaele
Via Olgettina 58,20132, Milan, Italy