title: Functional contribution of the transcription factor ATF4 to the pathogenesis of amyotrophic lateral sclerosis.
abstract: Endoplasmic reticulum (ER) stress represents an early pathological event in amyotrophic lateral sclerosis (ALS). ATF4 is a key ER stress transcription factor that plays a role in both adaptation to stress and the activation of apoptosis. Here we investigated the contribution of ATF4 to ALS. ATF4 deficiency reduced the rate of birth of SOD1(G86R) transgenic mice. The fraction of ATF4(-/-)-SOD1(G85R) transgenic mice that were born are more resistant to develop ALS, leading to delayed disease onset and prolonged life span. ATF4 deficiency completely attenuated the induction of pro-apoptotic genes, including BIM and CHOP, and also led to quantitative changes in the ER protein homeostasis network. Unexpectedly, ATF4 deficiency enhanced mutant SOD1 aggregation at the end stage of the disease. Studies in the motoneuron cell line NSC34 demonstrated that knocking down ATF4 enhances mutant SOD1 aggregation possibly due to alteration in the redox status of the cell. Our results support a functional role of ATF4 in ALS, offering a novel target for disease intervention.
authors.affiliation: Neurounion Biomedical Foundation, Santiago, Chile. soledad.matus@neurounion.com
authors.forename: Soledad
authors.initials: S
authors.lastname: Matus
authors.forename: Estefanía
authors.initials: E
authors.lastname: Lopez
authors.forename: Vicente
authors.initials: V
authors.lastname: Valenzuela
authors.forename: Melissa
authors.initials: M
authors.lastname: Nassif
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
mesh_terms: D051701:Activating Transcription Factor 4 / Q000172:deficiency / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005786:Gene Expression Regulation / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D020125:Mutation, Missense / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: C081452:Atf4 protein, mouse; D017931:DNA Primers; D051701:Activating Transcription Factor 4; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1