Dyskinesic Drosophila: using the fruit fly as a model to study hyperkinetic movement disorders

Maintaining control over voluntary movements is critical for human wellbeing, yet this ability is perturbed in many neurological diseases. One class of such diseases are dyskinesias, characterised by involuntary transient or sustained muscle contractions. While altered synaptic transmission and plasticity in sensorimotor centres such as the cerebellum and basal ganglia have been implicated in dyskinesia, the underlying molecular and cellular basis of these disorders remains unclear. We are addressing this issue using a novel Drosophila model of dyskinesia caused by a gain-of-function mutation in the hSlo1 calcium-activated BK potassium channel. We have found that insertion of the corresponding single base pair mutation into the Drosophila genome profoundly alters motor control and action selection in a manner that mimics dyskinesia. By combining genetic strategies to spatially manipulate BK channel expression with RNAseq and follow-up screens for epistatic modifiers, we aim to define the key cell-types and molecular pathways that link enhanced BK channel function to pathological changes in motor control.  

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