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.
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA; The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Knight
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
authors.forename: Shusei
authors.initials: S
authors.lastname: Hamamichi
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
authors.forename: Rami R
authors.initials: RR
authors.lastname: Ajjuri
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Mazzulli
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
authors.forename: Mike W
authors.initials: MW
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
authors.forename: J Gavin
authors.initials: JG
authors.lastname: Daigle
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
authors.forename: Akeem R
authors.initials: AR
authors.lastname: Borom
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
authors.forename: Lindsay R
authors.initials: LR
authors.lastname: Roberts
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
authors.forename: S Kyle
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: DeLeon
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Coralie
authors.initials: C
authors.lastname: Viollet-Djelassi
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
authors.forename: Janis M
authors.initials: JM
authors.lastname: O'Donnell
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA; Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA; Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: gcaldwel@ua.edu.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
mesh_terms: D000375:Aging; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000166:cytology / Q000378:metabolism*; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005956:Glucose-6-Phosphate Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D016207:Cytokines; D029721:Drosophila Proteins; D051858:Forkhead Transcription Factors; D055504:Insulin Receptor Substrate Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051844:alpha-Synuclein; C120233:chico protein, Drosophila; C108831:daf-16 protein, C elegans; D007334:Insulin-Like Growth Factor I; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin; D005956:Glucose-6-Phosphate Isomerase; C554960:Gpi1 protein, mouse; D005947:Glucose