Spinocerebellar ataxias (SCAs) are autosomal dominant neurodegenerative conditions characterized by cerebellar atrophy causing progressive motor incoordination (ataxia). Mechanistic insights into disease pathogenesis have been slow in coming, largely because many of the genes mutated encode for proteins whose function is still unknown. Consequently, no disease modifying therapy exists for these invalidating conditions. Recent data show that increased activity of one particular ion channel, TRPC3, which is highly enriched in the cerebellum and in cerebellar Purkinje cells in particular, is the cause of SCA41 and may also represent a shared mechanism in many SCAs. The TRPC3 gain-of-function in turn leads to impaired firing and neuronal toxicity. In this proposal we will take advantage of the ?moonwalker? mutant, a mouse model of SCA41 to test the therapeutic efficacy of TRPC3 blockade in slowing or stopping the course of the disease. The effectiveness of the treatment will be evaluated by quantification of behavioral, electrophysiological and pathological parameters.
Cerebellar ataxias are debilitating neurodegenerative disorders linked to overt cell loss in the cerebellum and for which there are no treatment options. Here we propose that some ataxic phenotypes may be caused by reversible functional impairment of cerebellar Purkinje neurons, which can be due to deranged signaling involving a class of calcium channels named TRPC3. We will take advantage of an animal model of ataxia 41, which is caused by a TRPC3 gain-of-function mutation, to test the therapeutic potential of the TRPC3 blocker Pyr3 in reversing the defining features of ataxia.
| Edamakanti, Chandrakanth Reddy; Do, Jeehaeh; Didonna, Alessandro et al. (2018) Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1. J Clin Invest 128:2252-2265 |
