The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models

Adam L. Knight, Xiaohui Yan, Shusei Hamamichi, Rami R. Ajjuri, Joseph R. Mazzulli, Mike W. Zhang, J. Gavin Daigle, Siyuan Zhang, Akeem R. Borom, Lindsay R. Roberts, S. Kyle Lee, Susan M. DeLeon, Coralie Viollet-Djelassi, Dimitri Krainc, Janis M. O'Donnell, Kim A. Caldwell, Guy A. Caldwell*

*Corresponding author for this work

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)145-157
Number of pages13
JournalCell Metabolism
Volume20
Issue number1
DOIs
StatePublished - Jul 1 2014

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    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 Metabolism, 20(1), 145-157. https://doi.org/10.1016/j.cmet.2014.04.017