Molecular Horizons Seminar with Dr Carola Venturini

Molecular Horizons Seminar with Dr Collin Anderson

Degenerative cerebellar ataxias affect 1 in every 5000 people worldwide, usually featuring cerebellar Purkinje cell (PC) loss, leading to progressive loss of coordination. We hypothesised that neuromodulation targeting the deep cerebellar nuclei, downstream from PC loss, might be able to reduce motor symptoms across a variety of ataxias. We tested this hypothesis using the shaker rat, a spontaneous model of PC loss and ataxia.

In contrast to deep brain stimulation (DBS) for Parkinson’s disease, we found that standard, 100+ Hz stimulation was ineffective in treating ataxia. However, we found that low-frequency stimulation (30 Hz) reduced ataxia and cerebellar tremor. While cerebellar stimulation might be able to function as a catch-all therapy for degenerative ataxias, there exists a subset of genetic ataxia for which gene replacement therapies may provide a more attractive treatment option. Having found evidence that the shaker phenotype is caused by a loss-of-function mutation in Slc9a6, which causes Christianson syndrome, we developed an adeno-associated virus targeting expression of Slc9a6 to PCs. We found that minimal gene replacement reduced ataxia and tremor to a greater degree than neuromodulatory strategies. Future work will focus on optimisation of neuromodulatory strategies and development of a human treatment-specific viral construct for Christianson syndrome.