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) |
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Pages (from-to) | 145-157 |
Number of pages | 13 |
Journal | Cell Metabolism |
Volume | 20 |
Issue number | 1 |
DOIs | |
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