title: Endogenous TDP-43, but not FUS, contributes to stress granule assembly via G3BP.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of upper and lower motor neurons, a cell type that is intrinsically more vulnerable than other cell types to exogenous stress. The interplay between genetic susceptibility and environmental exposures to toxins has long been thought to be relevant to ALS. One cellular mechanism to overcome stress is the formation of small dense cytoplasmic domains called stress granules (SG) which contain translationally arrested mRNAs. TDP-43 (encoded by TARDBP) is an ALS-causative gene that we have previously implicated in the regulation of the core stress granule proteins G3BP and TIA-1. TIA-1 and G3BP localize to SG under nearly all stress conditions and are considered essential to SG formation. Here, we report that TDP-43 is required for proper SG dynamics, especially SG assembly as marked by the secondary aggregation of TIA-1. We also show that SG assembly, but not initiation, requires G3BP. Furthermore, G3BP can rescue defective SG assembly in cells depleted of endogenous TDP-43. We also demonstrate that endogenous TDP-43 and FUS do not have overlapping functions in this cellular process as SG initiation and assembly occur normally in the absence of FUS. Lastly, we observe that SG assembly is a contributing factor in the survival of neuronal-like cells responding to acute oxidative stress. These data raise the possibility that disruptions of normal stress granule dynamics by loss of nuclear TDP-43 function may contribute to neuronal vulnerability in ALS.
authors.affiliation: Centre d'Excellence en Neuromique de l'Université de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Departments of Medicine and Biochemistry, Université de Montréal, 1560 rue Sherbrooke Est, Montréal, QC H2L 4M1, Canada.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Aulas
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Stabile
authors.forename: Christine
authors.initials: C
authors.lastname: Vande Velde
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000378:metabolism*; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D018384:Oxidative Stress / Q000502:physiology*; D000075223:Poly-ADP-Ribose Binding Proteins; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; D034702:RNA-Binding Protein FUS / Q000378:metabolism; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D000067776:RNA Recognition Motif Proteins; D034702:RNA-Binding Protein FUS; D004265:DNA Helicases; C116070:G3BP1 protein, human; D020365:RNA Helicases