Novel Drosophila model for parkinsonism by targeting phosphoglycerate kinase

Patients with Parkinson’s disease (PD) show a common progressive neurodegenerative movement disordercharacterized by rigidity, tremors, postural instability, and bradykinesia due to the loss of dopaminergic neuronsin the substantia nigra, and is often accompanied by several non-motor symptoms, called parkinsonism. Severallines of recent evidence support the hypothesis that mutations in the gene encoding phosphoglycerate kinase(PGK) play an important role in the PD mechanism. PGK is a key enzyme in the glycolytic pathway that catalyzesthe reaction from 1,3-diphosphoglycerate to 3-phosphoglycerate. We herein established a parkinsonism modeltargeting Drosophila Pgk. Dopaminergic (DA) neuron-specific Pgk knockdown lead to locomotive defects in bothyoung and aged adult flies and was accompanied by progressive DA neuron loss with aging. Pgk knockdown inDA neurons decreased dopamine levels in the central nervous system (CNS) of both young and aged adult flies.These phenotypes are similar to the defects observed in human PD patients, suggesting that the Pgk knockdownflies established herein are a promising model for parkinsonism. Furthermore, pan-neuron-specific Pgk knockdowninduced low ATP levels and the accumulation of reactive oxygen species (ROS) in the CNS of third instarlarvae. Collectively, these results indicate that a failure in the energy production system of Pgk knockdown fliescauses locomotive defects accompanied by neuronal dysfunction and degeneration in DA neurons