GABAergic neuronal dysfunction underlies tremor in 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, Feature Learning-based Leg segmentation and Tracking (FLLIT), we previously characterised gait and tremor signatures in a Drosophila model for spinocerebellar ataxia 3 (SCA3) and found them to be analogous to those in 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 led to tremor, indicating their important role in adult motor control. RNA-sequencing and functional experiments showed that dysfunction of GABAergic neurons, and not that of other neurotransmitter populations tested, causes tremor. Finally, we identified a small subset of ∼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.