title: Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2.
abstract: The RNA-processing protein TDP-43 is central to the pathogenesis of amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron (MN) disease. TDP-43 is conserved in Drosophila, where it has been the topic of considerable study, but how TDP-43 mutations lead to age-dependent neurodegeneration is unclear and most approaches have not directly examined changes in MN morphology with age. We used a mosaic approach to study age-dependent MN loss in the adult fly leg where it is possible to resolve single motor axons, NMJs and active zones, and perform rapid forward genetic screens. We show that expression of TDP-43(Q331K) caused dying-back of NMJs and axons, which could not be suppressed by mutations that block Wallerian degeneration. We report the identification of three genes that suppress TDP-43 toxicity, including shaggy/GSK3, a known modifier of neurodegeneration. The two additional novel suppressors, hat-trick and xmas-2, function in chromatin modeling and RNA export, two processes recently implicated in human ALS. Loss of shaggy/GSK3, hat-trick, or xmas-2 does not suppress Wallerian degeneration, arguing TDP-43(Q331K)-induced and Wallerian degeneration are genetically distinct processes. In addition to delineating genetic factors that modify TDP-43 toxicity, these results establish the Drosophila adult leg as a valuable new tool for the in vivo study of adult MN phenotypes.
authors.affiliation: Howard Hughes Medical Institute and Department of Neurobiology, LRB-740A1, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01655, USA; Department of Neurology, S5-755, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA; Signalling ISP, The Babraham Institute, Cambridge CB22 3AT, UK. Electronic address: jemeen.sreedharan@babraham.ac.uk.
authors.forename: Jemeen
authors.initials: J
authors.lastname: Sreedharan
authors.affiliation: Howard Hughes Medical Institute and Department of Neurobiology, LRB-740A1, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01655, USA.
authors.forename: Lukas J
authors.initials: LJ
authors.lastname: Neukomm
authors.affiliation: Department of Neurology, S5-755, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.affiliation: Howard Hughes Medical Institute and Department of Neurobiology, LRB-740A1, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01655, USA. Electronic address: marc.freeman@umassmed.edu.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Freeman
mesh_terms: D000375:Aging; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D007814:Larva / Q000235:genetics / Q000502:physiology; D009046:Motor Neurons / Q000502:physiology*; D009410:Nerve Degeneration / Q000235:genetics* / Q000503:physiopathology
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C000589036:TBPH protein, Drosophila