title: Preservation of forelimb function by UPF1 gene therapy in a rat model of TDP-43-induced motor paralysis.
abstract: Nonsense-mediated mRNA decay (NMD) is an RNA surveillance mechanism that requires upframeshift protein 1 (UPF1). This study demonstrates that human UPF1 exerts protective effects in a rat paralysis model based on the amyotrophic lateral sclerosis (ALS)-associated protein, TDP-43 (transactive response DNA-binding protein 43 kDa). An adeno-associated virus vector (AAV9) was used to express TDP-43 throughout the spinal cord of rats, inducing reproducible limb paralysis, to recapitulate the paralysis in ALS. We selected UPF1 for therapeutic testing based on a genetic screen in yeast. The expression of human TDP-43 or human UPF1 in the spinal cord was titrated to less than twofold over the respective endogenous level. AAV9 human mycUPF1 clearly improved overall motor scores in rats also expressing TDP-43. The gene therapy effect of mycUPF1 was specific and reproducible compared with groups receiving either empty vector or green fluorescent protein vector controls. The gene therapy maintained forelimb motor function in rats that would otherwise become quadriplegic. This work helps validate UPF1 as a novel therapeutic for ALS and other TDP-43-related diseases and may implicate UPF1 and NMD involvement in the underlying disease mechanisms.
authors.affiliation: Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Jackson
authors.affiliation: Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Dayton
authors.affiliation: Department of Animal Resources, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Orchard
authors.affiliation: Department of Biological Sciences, Wright State University, Dayton, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ju
authors.affiliation: Department of Biochemistry and Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Ringe
authors.affiliation: 1] Department of Biochemistry and Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA, USA [2] Department of Neurology and Neuroscience, Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Petsko
authors.affiliation: 1] Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA [2] Center for RNA Biology, University of Rochester, Rochester, NY, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Maquat
authors.affiliation: Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Klein
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology / Q000628:therapy*; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005552:Forelimb / Q000503:physiopathology*; D015316:Genetic Therapy; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009043:Motor Activity; D010243:Paralysis / Q000628:therapy; D020365:RNA Helicases; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human; D015534:Trans-Activators; D020365:RNA Helicases; C101828:UPF1 protein, human