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

doi:10.1016/j.cmet.2014.04.017

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

Neurology

Research output: Contribution to journal › Article › peer-review

83 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 language	English (US)
Pages (from-to)	145-157
Number of pages	13
Journal	Cell Metabolism
Volume	20
Issue number	1
DOIs	https://doi.org/10.1016/j.cmet.2014.04.017
State	Published - Jul 1 2014

Funding

We are grateful to all members of the Caldwell and O’Donnell labs for their collegiality and collective teamwork. Special thanks to Laura Berkowitz for her invaluable contributions and Chris Link and Richard Morimoto for the Aβ paralysis and Q82::GFP strains, respectively. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This research was funded by grants from the National Institutes of Health (R15 NS075684-01 to G.A.C. and R15 NS078728 to J.M.O.). Other support came from a Howard Hughes Medical Institute Undergraduate Science Program Grant to The University of Alabama (A.R.B., S.K.L., and S.M.D.), as well as the Parkinson’s Support Group of Huntsville (L.R.R.) and the Parkinson’s Association of Alabama (A.L.K. and M.W.Z.).

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

@article{29eeed8b9ba64fe09512e1741d786583,

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

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.",

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

note = "Funding Information: We are grateful to all members of the Caldwell and O{\textquoteright}Donnell labs for their collegiality and collective teamwork. Special thanks to Laura Berkowitz for her invaluable contributions and Chris Link and Richard Morimoto for the Aβ paralysis and Q82::GFP strains, respectively. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This research was funded by grants from the National Institutes of Health (R15 NS075684-01 to G.A.C. and R15 NS078728 to J.M.O.). Other support came from a Howard Hughes Medical Institute Undergraduate Science Program Grant to The University of Alabama (A.R.B., S.K.L., and S.M.D.), as well as the Parkinson{\textquoteright}s Support Group of Huntsville (L.R.R.) and the Parkinson{\textquoteright}s Association of Alabama (A.L.K. and M.W.Z.). ",

year = "2014",

month = jul,

day = "1",

doi = "10.1016/j.cmet.2014.04.017",

language = "English (US)",

volume = "20",

pages = "145--157",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "1",

}

Knight, AL, Yan, X, Hamamichi, S, Ajjuri, RR, Mazzulli, JR, Zhang, MW, Daigle, JG, Zhang, S, Borom, AR, Roberts, LR, Lee, SK, DeLeon, SM, Viollet-Djelassi, C, Krainc, D, O'Donnell, JM, Caldwell, KA & Caldwell, GA 2014, 'The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models', Cell Metabolism, vol. 20, no. 1, pp. 145-157. https://doi.org/10.1016/j.cmet.2014.04.017

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, Joseph R.

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.

N1 - Funding Information: We are grateful to all members of the Caldwell and O’Donnell labs for their collegiality and collective teamwork. Special thanks to Laura Berkowitz for her invaluable contributions and Chris Link and Richard Morimoto for the Aβ paralysis and Q82::GFP strains, respectively. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This research was funded by grants from the National Institutes of Health (R15 NS075684-01 to G.A.C. and R15 NS078728 to J.M.O.). Other support came from a Howard Hughes Medical Institute Undergraduate Science Program Grant to The University of Alabama (A.R.B., S.K.L., and S.M.D.), as well as the Parkinson’s Support Group of Huntsville (L.R.R.) and the Parkinson’s Association of Alabama (A.L.K. and M.W.Z.).

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.

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JO - Cell Metabolism

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ER -

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

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