THE GLYCOLYTIC ENZYME, GPI-1, IS A FUNCTIONALLY CONSERVED MODIFIER OF DOPAMINERIGIC NEURODEGENERATION IN PARKINSON’S MODELS[GC1]

Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and lifespan extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using datasets of established daf-2 /IIS-signaling components in Caenorhabditis elegans , we conducted systematic RNAi screens in worms to select for daf-2 -assoicated genetic modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson’s disease. An outcome of this strategy was the identification of gpi-1 /GPI, an enzyme in glucose metabolism, as a daf-2 -regulated modifier that acts independent of the downstream cytoprotective transcription factor, DAF-16/FOXO, to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from α-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.