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 language | English (US) |
|---|---|
| Pages (from-to) | 145-157 |
| Number of pages | 13 |
| Journal | Cell Metabolism |
| Volume | 20 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 1 2014 |
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ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology
Cite this
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The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models. / Knight, Adam L.; Yan, Xiaohui; Hamamichi, Shusei; Ajjuri, Rami R.; Mazzulli, Joe; Zhang, Mike W.; Daigle, J. Gavin; Zhang, Siyuan; Borom, Akeem R.; Roberts, Lindsay R.; Lee, S. Kyle; DeLeon, Susan M.; Viollet-Djelassi, Coralie; Krainc, Dimitri; O'Donnell, Janis M.; Caldwell, Kim A.; Caldwell, Guy A.
In: Cell Metabolism, Vol. 20, No. 1, 01.07.2014, p. 145-157.Research output: Contribution to journal › Article
TY - JOUR
T1 - The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models
AU - Knight, Adam L.
AU - Yan, Xiaohui
AU - Hamamichi, Shusei
AU - Ajjuri, Rami R.
AU - Mazzulli, Joe
AU - Zhang, Mike W.
AU - Daigle, J. Gavin
AU - Zhang, Siyuan
AU - Borom, Akeem R.
AU - Roberts, Lindsay R.
AU - Lee, S. Kyle
AU - DeLeon, Susan M.
AU - Viollet-Djelassi, Coralie
AU - Krainc, Dimitri
AU - O'Donnell, Janis M.
AU - Caldwell, Kim A.
AU - Caldwell, Guy A.
PY - 2014/7/1
Y1 - 2014/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84904035981&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904035981&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2014.04.017
DO - 10.1016/j.cmet.2014.04.017
M3 - Article
VL - 20
SP - 145
EP - 157
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 1
ER -