Reduced expression of Pss gene in Drosophila cortex glia causes dopaminergic cell death

BackgroundParkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons. While abnormal protein aggregation has been classically implicated in PD, increasing evidence suggests that lipid dysregulation may also contribute to neuronal vulnerability. Recent studies have begun to link abnormal phosphatidylserine (PS) metabolism to mitochondrial impairment and dopaminergic neuron loss in PD, yet the underlying cellular mechanisms remain poorly defined.ObjectiveThis study aimed to determine how impaired PS synthesis in cortex glia affects mitochondrial function, oxidative stress, and dopaminergic neuron survival, using a Drosophila model of glia-specific Phosphatidylserine synthase (Pss) knockdown.MethodsTo dissect the glial contribution to PS-related neurodegeneration, we employed a Drosophila model in which the Pss gene was selectively knocked down in cortex glia using the GAL4-UAS system. We evaluated PD-like phenotypes by assessing the number of dopaminergic neurons in the PPL1 and PPL2 clusters, as well as locomotor activity and lifespan, following glia-specific knockdown of Pss gene.ResultsCortex glia-specific knockdown of Pss impaired locomotion and reduced lifespan in flies, indicating a systemic decline in neuronal and mitochondrial function. Pss knockdown reduced mitochondrial transcription factor A (Tfam) expression, disrupted mitochondrial gene expression, and elevated ROS levels. Western blot analysis also revealed reduced AKT phosphorylation without changes in total AKT. These results ultimately lead to loss of dopaminergic neurons.ConclusionsThese findings establish a mechanistic link among abnormal PS metabolism, impaired AKT signaling, mitochondrial dysfunction, and dopaminergic neuron loss. Our study provides novel evidence that glia-driven abnormalities in PS metabolism may cause PD-like neurodegeneration, offering mechanistic insights and potential therapeutic targets.