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

Cell Metab. 2014 Jul 1;20(1):145-57. doi: 10.1016/j.cmet.2014.04.017. Epub 2014 May 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / antagonists & inhibitors
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Cells, Cultured
  • Cytokines / antagonists & inhibitors
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Dopaminergic Neurons / cytology
  • Dopaminergic Neurons / metabolism*
  • Drosophila / metabolism
  • Drosophila Proteins / antagonists & inhibitors
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Forkhead Transcription Factors / metabolism
  • Glucose / metabolism
  • Glucose-6-Phosphate Isomerase / antagonists & inhibitors
  • Glucose-6-Phosphate Isomerase / genetics
  • Glucose-6-Phosphate Isomerase / metabolism*
  • Glycolysis
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • Male
  • Mice
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptor, Insulin / antagonists & inhibitors
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Signal Transduction
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • Cytokines
  • Drosophila Proteins
  • Forkhead Transcription Factors
  • Insulin Receptor Substrate Proteins
  • RNA, Small Interfering
  • Transcription Factors
  • alpha-Synuclein
  • chico protein, Drosophila
  • daf-16 protein, C elegans
  • Insulin-Like Growth Factor I
  • DAF-2 protein, C elegans
  • Receptor, Insulin
  • Glucose-6-Phosphate Isomerase
  • Gpi1 protein, mouse
  • Glucose