Dysfunction of GABAergic neurons in the adult ventral nerve cord underlies SCA3-associated tremor in Drosophila melanogaster [rna0426]

ABSTRACT: Tremor is a common movement disorder associated with several neurodegenerative diseases. Despite its prevalence, its underlying mechanisms are not well understood. We previously examined motor defects in a Drosophila model of Machado Joseph disease (MJD), also known as Spinocerebellar ataxia 3 (SCA3). We found that the SCA3 fly model exhibits distinct gait and tremor signatures analogous to human SCA3 motor dysfunctions, and can hence be used to investigate the neurogenetic mechanisms of SCA3 tremor1. Here, we identify and characterise the neuronal populations involved in SCA3-associated tremor. Through a genetic screen, we identified a population of neurons in the ventral nerve cord (VNC) whose dysfunction is sufficient to generate tremor. Adult-onset expression of mutant ATXN3 in a subset of these neurons leads to tremor. RNAseq and functional experiments provide evidence that dysfunction of GABAergic neurons, and not other neurotransmitter populations tested, causes tremor. We found that a subset of ~30 of these VNC neurons, ~80% of which are GABAergic, are required for smooth motor control of walking in the fly, as their dysfunction causes tremor. Therefore, tremor in the SCA3 fly model is primarily caused by dysfunction of GABAergic neurons in the adult ventral nerve cord.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE275250 | GEO | 2026/08/29

REPOSITORIES: GEO