The Glycolytic Enzyme, GPI, Is a Functionally Conserved Modifier of Dopaminergic Neurodegeneration in Parkinson’s Models

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 inves...

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Published in:Cell metabolism 2014-07, Vol.20 (1), p.145-157
Main Authors: Knight, Adam L., Yan, Xiaohui, Hamamichi, Shusei, Ajjuri, Rami R., Mazzulli, Joseph R., 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.
Format: Article
Language:English
Subjects:
Aging
alpha-Synuclein - chemistry
alpha-Synuclein - metabolism
Animals
Caenorhabditis elegans
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
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
Receptor, Insulin - antagonists & inhibitors
Receptor, Insulin - genetics
Receptor, Insulin - metabolism
RNA Interference
RNA, Small Interfering - metabolism
Signal Transduction
Transcription Factors - antagonists & inhibitors
Transcription Factors - genetics
Transcription Factors - metabolism
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Summary: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. [Display omitted] •Insulin signaling modulates neurodegeneration in fly and worm Parkinson’s models•Reduced insulin-signaling screen reveals metabolic modifiers of protein misfolding•A glycolytic enzyme, GPI, is neuroprotective across worms, flies, and mouse neurons•GPI functions independently of DAF-16/FOXO to modulate proteostasis via glycolysis Knight et al. screened for modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson’s disease, in worms with decreased IIS signaling. They identify the glycolytic enzyme GPI, which plays a conserved DAF-16/FOXO-independent role in worms, flies, and primary mouse neurons, integrating metabolic regulation with proteotoxicity and dopaminergic neurodegeneration.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2014.04.017