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Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response

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  • Jennifer L Johnson
  • Loredana Stoica
  • Yuwei Liu
  • Ping Jun Zhu
  • Abhisek Bhattacharya
  • Shelly A Buffington
  • Redwan Huq
  • N Tony Eissa
  • Ola Larsson
  • Bo T Porse
  • Deepti Domingo
  • Urwah Nawaz
  • Renee Carroll
  • Lachlan Jolly
  • Tom S Scerri
  • Hyung-Goo Kim
  • Amanda Brignell
  • Matthew J Coleman
  • Ruth Braden
  • Usha Kini
  • Victoria Jackson
  • Anne Baxter
  • Melanie Bahlo
  • Ingrid E Scheffer
  • David J Amor
  • Michael S Hildebrand
  • Penelope E Bonnen
  • Christine Beeton
  • Jozef Gecz
  • Angela T Morgan
  • Mauro Costa-Mattioli
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In humans, disruption of nonsense-mediated decay (NMD) has been associated with neurodevelopmental disorders (NDDs) such as autism spectrum disorder and intellectual disability. However, the mechanism by which deficient NMD leads to neurodevelopmental dysfunction remains unknown, preventing development of targeted therapies. Here we identified novel protein-coding UPF2 (UP-Frameshift 2) variants in humans with NDD, including speech and language deficits. In parallel, we found that mice lacking Upf2 in the forebrain (Upf2 fb-KO mice) show impaired NMD, memory deficits, abnormal long-term potentiation (LTP), and social and communication deficits. Surprisingly, Upf2 fb-KO mice exhibit elevated expression of immune genes and brain inflammation. More importantly, treatment with two FDA-approved anti-inflammatory drugs reduced brain inflammation, restored LTP and long-term memory, and reversed social and communication deficits. Collectively, our findings indicate that impaired UPF2-dependent NMD leads to neurodevelopmental dysfunction and suggest that anti-inflammatory agents may prove effective for treatment of disorders with impaired NMD.

Original languageEnglish
JournalNeuron
Volume104
Issue number4
Pages (from-to)665-679.e8
ISSN0896-6273
DOIs
Publication statusPublished - 20 Nov 2019

    Research areas

  • autism, immune response, memory, mRNA quality control, neurodevelopmental disorders, speech disorder

ID: 58182026