Overexpression of α-synuclein in Pigment Dispersing Factor neurons alters sleep–wake pattern by regulating lipid metabolism in Drosophila

Abstract Parkinson’s disease (PD) is a complex neurodegenerative disorder, characterized by the aggregation of α-synuclein (α-syn). Current research increasingly indicates the prevalence of sleep–wake disorders in early-stage PD, although the underlying pathogenic mechanisms remain unclear. In this study, transgenic Drosophila models were utilized to observe excessive daytime sleepiness and impaired anticipation in flies overexpressing α-syn in pan-neurons and circadian clock neurons. Additionally, deficits in projection of Pigment Dispersing Factor (PDF) neuron terminals, which are involved in Drosophila sleep and circadian rhythm, were identified. An imbalance in lipid metabolism homeostasis was detected in the brains of α-syn overexpressing mutants. Ultimately, the inhibition of Sterol Regulatory Element-Binding Protein (SREBP) activity led to an improvement in the reduced daytime sleep duration phenotype. Our results suggest that lipid pathways play a role in sleep–wake disorders triggered by α-syn mutation and aggregation, thereby providing valuable insights into potential therapeutic avenues for disrupted sleep patterns associated with PD.