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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.
Cell metabolism, 07/2014, Letnik: 20, Številka: 1Journal Article
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.
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in: SICRIS
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