Titre
Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2.
Type
article
Institution
Externe
Périodique
Auteur(s)
Sreedharan, J.
Auteure/Auteur
Neukomm, L.J.
Auteure/Auteur
Brown, R.H.
Auteure/Auteur
Freeman, M.R.
Auteure/Auteur
Liens vers les personnes
ISSN
1879-0445
Statut éditorial
Publié
Date de publication
2015-08-17
Volume
25
Numéro
16
Première page
2130
Dernière page/numéro d’article
2136
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
Sujets
PID Serval
serval:BIB_9CA3141BA8CA
PMID
URL éditeur
Open Access
Oui
Date de création
2023-12-08T08:45:55.911Z
Date de création dans IRIS
2025-05-21T04:52:56Z