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Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2

2015; Elsevier BV; Volume: 25; Issue: 16 Linguagem: Inglês

10.1016/j.cub.2015.06.045

1879-0445

Jemeen Sreedharan, Lukas J. Neukomm, Robert H. Brown, Marc Freeman,

Neurological diseases and metabolism

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 [1Neumann M. Sampathu D.M. Kwong L.K. Truax A.C. Micsenyi M.C. Chou T.T. Bruce J. Schuck T. Grossman M. Clark C.M. et al.Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.Science. 2006; 314: 130-133Crossref PubMed Scopus (4059) Google Scholar, 2Arai T. Hasegawa M. Akiyama H. Ikeda K. Nonaka T. Mori H. Mann D. Tsuchiya K. Yoshida M. Hashizume Y. Oda T. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.Biochem. Biophys. Res. Commun. 2006; 351: 602-611Crossref PubMed Scopus (1699) Google Scholar, 3Sreedharan J. Blair I.P. Tripathi V.B. Hu X. Vance C. Rogelj B. Ackerley S. Durnall J.C. Williams K.L. Buratti E. et al.TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis.Science. 2008; 319: 1668-1672Crossref PubMed Scopus (1817) Google Scholar, 4Kabashi E. Valdmanis P.N. Dion P. Spiegelman D. McConkey B.J. Vande Velde C. Bouchard J.P. Lacomblez L. Pochigaeva K. Salachas F. et al.TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.Nat. Genet. 2008; 40: 572-574Crossref PubMed Scopus (1151) Google Scholar]. 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 [5Casci I. Pandey U.B. A fruitful endeavor: modeling ALS in the fruit fly.Brain Res. 2015; 1607: 47-74Crossref PubMed Scopus (61) Google Scholar]. 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-43Q331K 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 [6Cohen P. Goedert M. GSK3 inhibitors: development and therapeutic potential.Nat. Rev. Drug Discov. 2004; 3: 479-487Crossref PubMed Scopus (647) Google Scholar]. The two additional novel suppressors, hat-trick and xmas-2, function in chromatin modeling and RNA export, two processes recently implicated in human ALS [7Chesi A. Staahl B.T. Jovičić A. Couthouis J. Fasolino M. Raphael A.R. Yamazaki T. Elias L. Polak M. Kelly C. et al.Exome sequencing to identify de novo mutations in sporadic ALS trios.Nat. Neurosci. 2013; 16: 851-855Crossref PubMed Scopus (102) Google Scholar, 8Kaneb H.M. Folkmann A.W. Belzil V.V. Jao L.E. Leblond C.S. Girard S.L. Daoud H. Noreau A. Rochefort D. Hince P. et al.Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis.Hum. Mol. Genet. 2014; 24: 1363-1373Crossref PubMed Scopus (96) Google Scholar]. Loss of shaggy/GSK3, hat-trick, or xmas-2 does not suppress Wallerian degeneration, arguing TDP-43Q331K-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.