Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1
| Autor: | Arpana Arjun, Dagmar Ringe, Eric J. Huang, Gregory A. Petsko, Yuxi Zhang, Steven Finkbeiner, Daniel Peisach, Xingli Li, Anthony Batarse, Haiyan Qiu, Hilary C. Archbold, Elizabeth M. H. Tank, Shulin Ju, Sami J. Barmada |
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| Rok vydání: | 2015 |
| Předmět: |
Cell Survival
RNA-binding protein Biology Neurodegenerative Models Biological RNA decay Pathogenesis Rare Diseases Models medicine Genetics Acquired Cognitive Impairment Humans 2.1 Biological and endogenous factors Amyotrophic lateral sclerosis Aetiology Alzheimer's Disease Related Dementias (ADRD) Neurons Multidisciplinary Neurodegeneration Amyotrophic Lateral Sclerosis neurodegeneration Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) FTD Biological Sciences medicine.disease Biological Stem Cell Research RNA Helicase A Nonsense Mediated mRNA Decay Brain Disorders Frontotemporal Dementia (FTD) Neuroprotective Agents RNA splicing Toxicity Neurological Trans-Activators Dementia RNA binding proteins ALS Neuroscience RNA Helicases Frontotemporal dementia |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 112, iss 25 Barmada, SJ; Ju, S; Arjun, A; Batarse, A; Archbold, HC; Peisach, D; et al.(2015). Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1. Proceedings of the National Academy of Sciences of the United States of America, 112(25), 7821-7826. doi: 10.1073/pnas.1509744112. UC San Francisco: Retrieved from: http://www.escholarship.org/uc/item/5dn3b2m6 |
| DOI: | 10.1073/pnas.1509744112. |
| Popis: | © 2015, National Academy of Sciences. All rights reserved. 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. |
| Databáze: | OpenAIRE |
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