Knight, A.L., Yan, X., Hamamichi, S., Ajjuri, R.R., Mazzulli, J.R., Zhang, M.W., Daigle, J.G., Zhang, S., Borom, A.R., Roberts, L.R., Lee, S.K., DeLeon, S.M., Viollet-Djelassi, C., Krainc, D., O'Donnell, J.M., Caldwell, K.A., Caldwell, G.A. (2014). The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models.  Cell Metab. 20(1): 145--157.

FBrf0225522

Research paper

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 data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated 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.

PMC4097176 (PMC) (EuropePMC)