title: Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation.
abstract: A functional genetic screen using loss-of-function and gain-of-function alleles was performed to identify modifiers of tau-induced neurotoxicity using the 2N/4R (full-length) isoform of wild-type human tau expressed in the fly retina. We previously reported eye pigment mutations, which create dysfunctional lysosomes, as potent modifiers; here, we report 37 additional genes identified from ∼1900 genes screened, including the kinases shaggy/GSK-3beta, par-1/MARK, CamKI and Mekk1. Tau acts synergistically with Mekk1 and p38 to down-regulate extracellular regulated kinase activity, with a corresponding decrease in AT8 immunoreactivity (pS202/T205), suggesting that tau can participate in signaling pathways to regulate its own kinases. Modifiers showed poor correlation with tau phosphorylation (using the AT8, 12E8 and AT270 epitopes); moreover, tested suppressors of wild-type tau were equally effective in suppressing toxicity of a phosphorylation-resistant S11A tau construct, demonstrating that changes in tau phosphorylation state are not required to suppress or enhance its toxicity. Genes related to autophagy, the cell cycle, RNA-associated proteins and chromatin-binding proteins constitute a large percentage of identified modifiers. Other functional categories identified include mitochondrial proteins, lipid trafficking, Golgi proteins, kinesins and dynein and the Hsp70/Hsp90-organizing protein (Hop). Network analysis uncovered several other genes highly associated with the functional modifiers, including genes related to the PI3K, Notch, BMP/TGF-β and Hedgehog pathways, and nuclear trafficking. Activity of GSK-3β is strongly upregulated due to TDP-43 expression, and reduced GSK-3β dosage is also a common suppressor of Aβ42 and TDP-43 toxicity. These findings suggest therapeutic targets other than mitigation of tau phosphorylation.
authors.affiliation: Department of Neurology, University of Texas Medical Branch, 301 University Blvd., MRB 10.138, Galveston, TX 77555, USA.
authors.forename: Surendra S
authors.initials: SS
authors.lastname: Ambegaokar
authors.forename: George R
authors.initials: GR
authors.lastname: Jackson
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000633:toxicity; D004331:Drosophila melanogaster / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005123:Eye / Q000187:drug effects / Q000473:pathology; D053263:Gene Regulatory Networks / Q000235:genetics*; D060045:Genes, Modifier / Q000235:genetics*; D016153:Genes, Suppressor; D005820:Genetic Testing; D023281:Genomics / Q000379:methods*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D050505:Mutant Proteins / Q000633:toxicity; D009498:Neurotoxins / Q000633:toxicity; D010455:Peptides / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D024801:Tauopathies / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism* / Q000633:toxicity
chemical_list: D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; D050505:Mutant Proteins; D009498:Neurotoxins; D010455:Peptides; D016875:tau Proteins; C097188:polyglutamine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D038362:Glycogen Synthase Kinase 3