title: Identification of genetic modifiers of TDP-43 neurotoxicity in Drosophila.
abstract: Cytosolic aggregation of the nuclear RNA-binding protein TDP-43 is a histopathologic signature of degenerating neurons in amyotrophic lateral sclerosis (ALS), and mutations in the TARDBP gene encoding TDP-43 cause dominantly inherited forms of this condition. To understand the relationship between TDP-43 misregulation and neurotoxicity, we and others have used Drosophila as a model system, in which overexpression of either wild-type TDP-43 or its ALS-associated mutants in neurons is sufficient to induce neurotoxicity, paralysis, and early death. Using microarrays, we have examined gene expression patterns that accompany TDP-43-induced neurotoxicity in the fly system. Constitutive expression of TDP-43 in the Drosophila compound eye elicited widespread gene expression changes, with strong upregulation of cell cycle regulatory genes and genes functioning in the Notch intercellular communication pathway. Inducible expression of TDP-43 specifically in neurons elicited significant expression differences in a more restricted set of genes. Genes that were upregulated in both paradigms included SpindleB and the Notch target Hey, which appeared to be a direct TDP-43 target. Mutations that diminished activity of Notch or disrupted the function of downstream Notch target genes extended the lifespan of TDP-43 transgenic flies, suggesting that Notch activation was deleterious in this model. Finally, we showed that mutation of the nucleoporin Nup50 increased the lifespan of TDP-43 transgenic flies, suggesting that nuclear events contribute to TDP-43-dependent neurotoxicity. The combined findings identified pathways whose deregulation might contribute to TDP-43-induced neurotoxicity in Drosophila.
authors.affiliation: Department of Human Oncology, Program in Molecular and Cellular Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhan
authors.forename: Keith A
authors.initials: KA
authors.lastname: Hanson
authors.forename: Sang Hwa
authors.initials: SH
authors.lastname: Kim
authors.forename: Apeksha
authors.initials: A
authors.lastname: Tare
authors.forename: Randal S
authors.initials: RS
authors.lastname: Tibbetts
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000633:toxicity*; D004330:Drosophila / Q000187:drug effects* / Q000235:genetics; D009420:Nervous System / Q000187:drug effects* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000633:toxicity*
chemical_list: D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins