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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 Metab. 20(1): 145--157.
FlyBase ID
FBrf0225522
Publication Type
Research paper
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.

Graphical Abstract
Obtained with permission from Cell Press.
PubMed ID
PubMed Central ID
PMC4097176 (PMC) (EuropePMC)
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Cell Metab.
    Title
    Cell Metabolism
    Publication Year
    2005-
    ISBN/ISSN
    1550-4131
    Data From Reference
    Alleles (4)
    Genes (4)
    Human Disease Models (1)
    Transgenic Constructs (2)