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.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging
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Animals
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Caenorhabditis elegans / metabolism
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Caenorhabditis elegans Proteins / antagonists & inhibitors
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism
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Cells, Cultured
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Cytokines / antagonists & inhibitors
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Cytokines / genetics
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Cytokines / metabolism
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Disease Models, Animal
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Dopaminergic Neurons / cytology
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Dopaminergic Neurons / metabolism*
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Drosophila / metabolism
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Drosophila Proteins / antagonists & inhibitors
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Forkhead Transcription Factors / metabolism
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Glucose / metabolism
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Glucose-6-Phosphate Isomerase / antagonists & inhibitors
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Glucose-6-Phosphate Isomerase / genetics
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Glucose-6-Phosphate Isomerase / metabolism*
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Glycolysis
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Insulin Receptor Substrate Proteins / genetics
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Insulin Receptor Substrate Proteins / metabolism
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Insulin-Like Growth Factor I / metabolism
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Male
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Mice
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Parkinson Disease / metabolism
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Parkinson Disease / pathology
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RNA Interference
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RNA, Small Interfering / metabolism
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Receptor, Insulin / antagonists & inhibitors
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Receptor, Insulin / genetics
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Receptor, Insulin / metabolism
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Signal Transduction
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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alpha-Synuclein / chemistry
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alpha-Synuclein / metabolism
Substances
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Caenorhabditis elegans Proteins
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Cytokines
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Drosophila Proteins
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Forkhead Transcription Factors
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Insulin Receptor Substrate Proteins
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RNA, Small Interfering
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Transcription Factors
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alpha-Synuclein
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chico protein, Drosophila
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daf-16 protein, C elegans
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Insulin-Like Growth Factor I
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DAF-2 protein, C elegans
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Receptor, Insulin
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Glucose-6-Phosphate Isomerase
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Gpi1 protein, mouse
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Glucose