title: Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1.
abstract: Over 30% of patients with amyotrophic lateral sclerosis (ALS) exhibit cognitive deficits indicative of frontotemporal dementia (FTD), suggesting a common pathogenesis for both diseases. Consistent with this hypothesis, neuronal and glial inclusions rich in TDP43, an essential RNA-binding protein, are found in the majority of those with ALS and FTD, and mutations in TDP43 and a related RNA-binding protein, FUS, cause familial ALS and FTD. TDP43 and FUS affect the splicing of thousands of transcripts, in some cases triggering nonsense-mediated mRNA decay (NMD), a highly conserved RNA degradation pathway. Here, we take advantage of a faithful primary neuronal model of ALS and FTD to investigate and characterize the role of human up-frameshift protein 1 (hUPF1), an RNA helicase and master regulator of NMD, in these disorders. We show that hUPF1 significantly protects mammalian neurons from both TDP43- and FUS-related toxicity. Expression of hUPF2, another essential component of NMD, also improves survival, whereas inhibiting NMD prevents rescue by hUPF1, suggesting that hUPF1 acts through NMD to enhance survival. These studies emphasize the importance of RNA metabolism in ALS and FTD, and identify a uniquely effective therapeutic strategy for these disorders.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109; sbarmada@umich.edu gpetsko@med.cornell.edu.
authors.forename: Sami J
authors.initials: SJ
authors.lastname: Barmada
authors.affiliation: Department of Biological Sciences, Wright State University, Dayton, OH 45435;
authors.forename: Shulin
authors.initials: S
authors.lastname: Ju
authors.affiliation: Institute of Neurologic Disease, The J. David Gladstone Institutes, San Francisco, CA 94158;
authors.forename: Arpana
authors.initials: A
authors.lastname: Arjun
authors.affiliation: Institute of Neurologic Disease, The J. David Gladstone Institutes, San Francisco, CA 94158;
authors.forename: Anthony
authors.initials: A
authors.lastname: Batarse
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Hilary C
authors.initials: HC
authors.lastname: Archbold
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Daniel
authors.initials: D
authors.lastname: Peisach
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Xingli
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Elizabeth M H
authors.initials: EM
authors.lastname: Tank
authors.affiliation: Department of Pathology, University of San Francisco, San Francisco, CA 94143;
authors.forename: Haiyan
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Department of Pathology, University of San Francisco, San Francisco, CA 94143;
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.affiliation: Departments of Biochemistry and Chemistry, Brandeis University, Waltham, MA 02454;
authors.forename: Dagmar
authors.initials: D
authors.lastname: Ringe
authors.affiliation: Departments of Biochemistry and Chemistry, Brandeis University, Waltham, MA 02454; Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10021; sbarmada@umich.edu gpetsko@med.cornell.edu.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Petsko
authors.affiliation: Institute of Neurologic Disease, The J. David Gladstone Institutes, San Francisco, CA 94158; Department of Neurology, University of California San Francisco Medical Center, San Francisco, CA 94143; Department of Physiology, University of California San Francisco Medical Center, San Francisco, CA 94143; Keck Program in Brain Cell Engineering, The J. David Gladstone Institutes, San Francisco, CA 94158; Taube/Koret Center for Neurodegenerative Disease Research, Hellman Foundation Alzheimer's Disease Research Program and Roddenberry Stem Cell Program, San Francisco, CA 94158.
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D002470:Cell Survival; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D059365:Nonsense Mediated mRNA Decay; D020365:RNA Helicases; D015534:Trans-Activators / Q000502:physiology*
chemical_list: D018696:Neuroprotective Agents; D015534:Trans-Activators; D020365:RNA Helicases; C101828:UPF1 protein, human
keywords: ALS; FTD; RNA binding proteins; RNA decay; neurodegeneration