Beyond dopaminergic neurons: neuronal contributions to sleep and motor dysfunction in a Drosophila model of Parkinson’s disease

Parkinson’s disease (PD) causes motor dysfunction and non-motor symptoms, including sleep disturbances. The strong association between REM sleep behavior disorder (RBD) and subsequent PD suggests a link between sleep and motor circuits. However, how distinct neuronal populations contribute to these manifestations remains poorly understood. Here, we asked whether α-synuclein–induced dysfunction across neuronal populations affects sleep and locomotion in Drosophila melanogaster. We expressed the PD-associated mutant α-synuclein A53T (α-SynA53T) pan-neuronally or in selected populations and analyzed sleep and locomotor coordination during aging. Pan-neuronal expression altered both sleep and locomotor coordination. Restricting α-SynA53T expression to dopaminergic neurons reproduced both phenotypes, with a stronger progression during aging. In contrast expression in the PPL1 and PPM3 dopaminergic clusters impaired motor coordination without affecting sleep. Expression in LPN neurons, a circadian sleep-promoting population, produced both sleep and locomotor alterations that persisted with age. Together, these findings show that PD-like motor and non-motor phenotypes depend on the neuronal population affected rather than uniformly arising from α-SynA53T expression in dopaminergic neurons. These results support a circuit-level contribution to PD symptoms and motivate ongoing studies to determine whether the distinct phenotypes are associated with differential neurodegeneration.