GABAergic neuronal dysfunction underlies tremor in a Drosophila model of Spinocerebellar ataxia 3

Tremor is a common movement disorder associated with several neurodegenerative diseases, yet its mechanisms are not well understood. Using a machine learning method, FLLIT, we previously characterised gait and tremor signatures in the Drosophila model for Spinocerebellar ataxia 3 (SCA3), and found them to be analogous to human SCA3. Here, we carried out a functional screen for neuronal populations that underlie tremor, and found that dysfunction of a specific population of neurons in the ventral nerve cord (VNC) is necessary and sufficient for tremor. Adult-onset expression of mutant ATXN3 in or genetic hypo-activation of these neurons leads to tremor, indicating their important role in adult motor control. RNAseq and functional experiments showed that dysfunction of GABAergic neurons, and not other neurotransmitter populations tested, causes tremor. Finally, we identified a small subset of approximately 30 predominantly GABAergic neurons within the adult VNC that are essential for smooth walking. This study demonstrates that tremor in SCA3 flies arises from GABAergic dysfunction, and that FLLIT can be used to dissect motor control mechanisms.