Inhibition of Upf2-dependent nonsense-mediated decay leads to behavioral and neurophysiological abnormalities by activating the immune response

Journal article


Johnson, Jennifer L., Stoica, Loredana, Liu, Yuwei, Zhu, Ping Jun, Bhattacharya, Abhisek, Buffington, Shelly A., Huq, Redwan, Eissa, N. Tony, Larsson, Ola, Porse, Bo T., Domingo, Deepti, Nawaz, Urwah, Carroll, Renee, Jolly, Lachlan, Scerri, Tom S., Kim, Hyung-Goo, Brignell, Amanda, Coleman, Matthew J., Braden, Ruth, ... Costa-Mattioli, Mauro. (2019). Inhibition of Upf2-dependent nonsense-mediated decay leads to behavioral and neurophysiological abnormalities by activating the immune response. Neuron. 104(4), pp. 665-679. https://doi.org/10.1016/j.neuron.2019.08.027
AuthorsJohnson, Jennifer L., Stoica, Loredana, Liu, Yuwei, Zhu, Ping Jun, Bhattacharya, Abhisek, Buffington, Shelly A., Huq, Redwan, Eissa, N. Tony, Larsson, Ola, Porse, Bo T., Domingo, Deepti, Nawaz, Urwah, Carroll, Renee, Jolly, Lachlan, Scerri, Tom S., Kim, Hyung-Goo, Brignell, Amanda, Coleman, Matthew J., Braden, Ruth, Kini, Usha, Jackson, Victoria, Baxter, Anne, Bahlo, Melanie, Scheffer, Ingrid E., Amor, David J., Hildebrand, Michael S., Bonnen, Penelope E., Beeton, Christine, Gecz, Jozef, Morgan, Angela T. and Costa-Mattioli, Mauro
Abstract

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.

KeywordsmRNA quality control; memory; autism; speech disorder; neurodevelopmental disorders; immune response
Year2019
JournalNeuron
Journal citation104 (4), pp. 665-679
PublisherCell Press
ISSN0896-6273
Digital Object Identifier (DOI)https://doi.org/10.1016/j.neuron.2019.08.027
Scopus EID2-s2.0-85074941034
Research or scholarlyResearch
Page range665-679
FunderAustralian Research Council (ARC)
National Health and Medical Research Council (NHMRC)
Publisher's version
License
All rights reserved
File Access Level
Controlled
Output statusPublished
Publication dates
Online01 Oct 2019
Publication process dates
Accepted14 Aug 2019
Deposited11 Jul 2021
ARC Funded ResearchThis output has been funded, wholly or partially, under the Australian Research Council Act 2001
Grant IDARC/DE160100620
NHMRC/1116976
NHMRC/1127144
NHMRC/1105008
Permalink -

https://acuresearchbank.acu.edu.au/item/8w583/inhibition-of-upf2-dependent-nonsense-mediated-decay-leads-to-behavioral-and-neurophysiological-abnormalities-by-activating-the-immune-response

Restricted files

Publisher's version

  • 66
    total views
  • 0
    total downloads
  • 1
    views this month
  • 0
    downloads this month
These values are for the period from 19th October 2020, when this repository was created.

Export as

Related outputs

Is language ability associated with behaviors of concern in autism? A systematic review
Chan, Charissa Ying Zhen, Williams, Katrina, May, Tamara, Wan, Wei Herng and Brignell, Amanda. (2023). Is language ability associated with behaviors of concern in autism? A systematic review. Autism Research. 16(2), pp. 250-270. https://doi.org/10.1002/aur.2855
Integrating interprofessional electronic medical record teaching in preregistration healthcare degrees : A case study
Lokmic-Tomkins, Zerina, Gray, Kathleen, Cheshire, Lisa, Parolini, Arno, Sharp, Megan, Tarrant, Bronwyn, Hill, Nicole, Rose, David, Webster, Marilyn, Virtue, Debra, Brignell, Amanda, Waring, Rebecca, Broussard, Fiona, Tsirgialos, Alex and Meng Cham, Kwang. (2023). Integrating interprofessional electronic medical record teaching in preregistration healthcare degrees : A case study. International Journal of Medical Informatics. 169, p. Article 104910. https://doi.org/10.1016/j.ijmedinf.2022.104910
Memantine for autism spectrum disorder
Brignell, Amanda, Marraffa, Catherine, Williams, Katrina and May, Tamara. (2022). Memantine for autism spectrum disorder. Cochrane Database of Systematic Reviews. 2022(8), p. Article CD013845. https://doi.org/10.1002/14651858.CD013845.pub2
Overall prognosis of preschool autism spectrum disorder diagnoses
Brignell, Amanda, Harwood, Rachael C., May, Tamara, Woolfenden, Susan, Montgomery, Alicia, Iorio, Alfonso and Williams, Katrina. (2022). Overall prognosis of preschool autism spectrum disorder diagnoses. Cochrane Database of Systematic Reviews. 2022(9), p. Article CD012749. https://doi.org/10.1002/14651858.CD012749.pub2
Delineating the autistic phenotype in children with neurofibromatosis type 1
Chisholm, Anita K., Haebich, Kristina M., Pride, Natalie A., Walsh, Karin S., Lami, Francesca, Ure, Alex, Maloof, Tiba, Brignell, Amanda, Rouel, Melissa, Granader, Yael, Maier, Alice, Barton, Belinda, Darke, Hayley, Dabscheck, Gabriel, Anderson, Vicki A., Williams, Katrina, North, Kathryn N. and Payne, Jonathon M.. (2022). Delineating the autistic phenotype in children with neurofibromatosis type 1. Molecular Autism. 13, p. Article 3. https://doi.org/10.1186/s13229-021-00481-3
Social motivation a relative strength in DYRK1A syndrome on a background of significant speech and language impairments
Morison, Lottie D., Braden, Ruth O., Amor, David J., Brignell, Amanda, van Bon, Bregje W. M. and Morgan, Angela T.. (2022). Social motivation a relative strength in DYRK1A syndrome on a background of significant speech and language impairments. European Journal of Human Genetics. 30(7), pp. 800-811. https://doi.org/10.1038/s41431-022-01079-w
Sex- and age-related differences in autistic behaviours in children with neurofibromatosis type 1
Chisholm, Anita K., Lami, Francesca, Haebich, Kristina M., Ure, Alex, Brignell, Amanda, Maloof, Tiba, Pride, Natalie A., Walsh, Karin S., Maier, Alice, Rouel, Melissa, Granader, Yael, Barton, Belinda, Darke, Hayley, Fuelscher, Ian, Dabscheck, Gabriel, Anderson, Vicki A., Williams, Katrina, North, Kathryn N. and Payne, Jonathan M.. (2022). Sex- and age-related differences in autistic behaviours in children with neurofibromatosis type 1. Journal of Autism and Developmental Disorders. 53, p. 2835–2850. https://doi.org/10.1007/s10803-022-05571-6
Memantine for autism spectrum disorder
Brignell, Amanda, Prakash, Chidambaram, Marraffa, Catherine, Williams, Katrina and May, Tamara. (2021). Memantine for autism spectrum disorder. Cochrane Database of Systematic Reviews. 2021(1), p. Article CD013845. https://doi.org/10.1002/14651858.CD013845
Identifying and supporting autistic preschoolers and their families
Brignell, Amanda, Cox, Georgina, Ure, Alexandra, Bernie, Charmaine and Williams, Katrina. (2021). Identifying and supporting autistic preschoolers and their families. Australian Journal of General Practice. 50(3), pp. 115-119. https://doi.org/10.31128/AJGP-11-20-5744
Interventions for children and adolescence who stutter : A systematic review, meta-analysis, and evidence map
Brignell, Amanda, Krahe, Michelle, Downes, Martin, Kefalianos, Elaina, Reilly, Sheena and Morgan, Angela. (2021). Interventions for children and adolescence who stutter : A systematic review, meta-analysis, and evidence map. Journal of Fluency Disorders. 70, p. Article 105843. https://doi.org/10.1016/j.jfludis.2021.105843
A modeling-guided case study of disordered speech in minimally verbal children with autism spectrum disorder
Chenausky Karen, V., Brignell, Amanda, Morgan Angela, T., Norton Andrea, C., Tager-Flusberg Helen, B., Schlaug, Gottfried and Guenther Frank, H.. (2021). A modeling-guided case study of disordered speech in minimally verbal children with autism spectrum disorder. American Journal of Speech-Language Pathology. 30(3S), pp. 1542-1557. https://doi.org/10.1044/2021_AJSLP-20-00121
A systematic review of interventions for adults who stutter
Brignell, Amanda, Krahe, Michelle, Downes, Martin, Kefalianos, Elaina, Reilly, Sheena and Morgan, Angela T.. (2020). A systematic review of interventions for adults who stutter. Journal of Fluency Disorders. 64, p. 105766. https://doi.org/10.1016/j.jfludis.2020.105766
Speech and language phenotype in Phelan-McDermid (22q13.3) syndrome
Brignell, Amanda, Gu, Conway, Holm, Alison, Carrigg, Bronwyn, Sheppard, Daisy A., Amor, David J. and Morgan, Angela T.. (2020). Speech and language phenotype in Phelan-McDermid (22q13.3) syndrome. European Journal of Human Genetics. 29(4), pp. 564-574. https://doi.org/10.1038/s41431-020-00761-1
Predicting speech-sound disorder outcomes in school-age children with hearing loss : The VicCHILD experience
St John, Miya, Columbus, Georgie, Brignell, Amanda, Carew, Peter, Skeat, Jemma, Reilly, Sheena and Morgan, Angela T.. (2020). Predicting speech-sound disorder outcomes in school-age children with hearing loss : The VicCHILD experience. International Journal of Language and Communication Disorders. 55(4), pp. 537-546. https://doi.org/10.1111/1460-6984.12536
No differences in code-related emergent literacy skills in well-matched 4-year-old children with and without ASD
Westerveld, Marleen F., Paynter, Jessica, Brignell, Amanda and Reilly, Sheena. (2020). No differences in code-related emergent literacy skills in well-matched 4-year-old children with and without ASD. Journal of Autism and Developmental Disorders. 50(8), pp. 3060-3065. https://doi.org/10.1007/s10803-020-04407-5
Factor analysis of signs of childhood apraxia of speech
Chenausky, Karen V., Brignell, Amanda, Morgan, Angela, Gagné, Danielle, Norton, Andrea, Tager-Flusberg, Helen, Schlaug, Gottfried, Shield, Aaron and Green, Jordan R.. (2020). Factor analysis of signs of childhood apraxia of speech. Journal of Communication Disorders. 87, p. 106033. https://doi.org/10.1016/j.jcomdis.2020.106033
Autism spectrum disorder prevalence in children aged 12–13 years from the longitudinal study of Australian children
May, Tamara, Brignell, Amanda and Williams, Katrina. (2020). Autism spectrum disorder prevalence in children aged 12–13 years from the longitudinal study of Australian children. Autism Research. 13(5), pp. 821-827. https://doi.org/10.1002/aur.2286
Preliminary evidence supports a range of speech sound interventions, but higher-quality studies are needed
Sanchez, Katherine, Brignell, Amanda and Morgan, Angela. (2019). Preliminary evidence supports a range of speech sound interventions, but higher-quality studies are needed. Evidence-based Communication Assessment and Intervention. 13(4), pp. 181-186. https://doi.org/10.1080/17489539.2019.1645982
Predictors and growth in receptive vocabulary from 4 to 8 years in children with and without autism spectrum disorder : A population-based study
Brignell, Amanda, May, Tamara, Morgan, Angela T. and Williams, Katrina. (2019). Predictors and growth in receptive vocabulary from 4 to 8 years in children with and without autism spectrum disorder : A population-based study. Autism: the international journal of research and practice. 23(5), pp. 1322-1334. https://doi.org/10.1177/1362361318801617
A systematic review and meta-analysis of the prognosis of language outcomes for individuals with autism spectrum disorder
Brignell, Amanda, Morgan, Angela T., Woolfenden, Susan, Klopper, Felicity, May, Tamara, Sarkozy, Vanessa and Williams, Katrina. (2018). A systematic review and meta-analysis of the prognosis of language outcomes for individuals with autism spectrum disorder. Autism & Developmental Language Impairments. 3, pp. 1-9. https://doi.org/10.1177/2396941518767610
Trends in the overlap of autism spectrum disorder and attention deficit hyperactivity disorder : Prevalence, clinical management, language and genetics
May, T., Brignell, A., Hawi, Z., Brereton, A., Tonge, B., Bellgrove, M. A. and Rinehart, N. J.. (2018). Trends in the overlap of autism spectrum disorder and attention deficit hyperactivity disorder : Prevalence, clinical management, language and genetics. Current Developmental Disorders Reports (online). 5(1), pp. 49-57. https://doi.org/10.1007/s40474-018-0131-8
Communication interventions for autism spectrum disorder in minimally verbal children
Brignell, A., Chenausky, K. V., Song, H., Zhu, J., Suo, C. and Morgan, A. T.. (2018). Communication interventions for autism spectrum disorder in minimally verbal children. Cochrane Database of Systematic Reviews. 2018(11), p. CD012324. https://doi.org/10.1002/14651858.CD012324.pub2
Patterns and predictors of language development from 4 to 7 years in verbal children with and without autism spectrum disorder
Brignell, Amanda, Williams, Katrina, Jachno, Kim, Prior, Margot, Reilly, Sheena and Morgan, Angela T.. (2018). Patterns and predictors of language development from 4 to 7 years in verbal children with and without autism spectrum disorder. Journal of Autism and Developmental Disorders. 48(10), pp. 3282-3295. https://doi.org/10.1007/s10803-018-3565-2
Characterization of speech and language phenotype in children with NRXN1 deletions
Brignell, Amanda, St John, Miya, Boys, Amber, Bruce, Amanda, Dinale, Carla, Pigdon, Lauren, Hildebrand, Michael S., Amor, David J. and Morgan, Angela T.. (2018). Characterization of speech and language phenotype in children with NRXN1 deletions. American Journal of Medical Genetics Part B : Neuropsychiatric Genetics. 177(8), pp. 700-708.
Parent-reported patterns of loss and gain in communication in 1- to 2-year-old children are not unique to autism spectrum disorder
Amanda Brignell, Katrina Williams, Margot Prior, Susan Donath, Sheena Reilly, Edith Bavin, Patricia Eadie and Angela Morgan. (2017). Parent-reported patterns of loss and gain in communication in 1- to 2-year-old children are not unique to autism spectrum disorder. Autism: the international journal of research and practice. 21(3), pp. 344-356. https://doi.org/10.1177/1362361316644729
Overall prognosis of preschool autism spectrum disorder diagnoses (Protocol)
Amanda Brignell, Natalia Albein-Urios, Susan Woolfenden, Andrew Hayen, Alfonso Iorio and Katrina Williams. (2017). Overall prognosis of preschool autism spectrum disorder diagnoses (Protocol). Cochrane Database of Systematic Reviews. 2017(8), pp. 1-18. https://doi.org/10.1002/14651858.CD012749
Autism spectrum disorder: Updated prevalence and comparison of two birth cohorts in a nationally representative Australian sample
Tamara May, Emma Sciberras, Amanda Brignell and Katrina Williams. (2017). Autism spectrum disorder: Updated prevalence and comparison of two birth cohorts in a nationally representative Australian sample. BMJ Open. 7(5), pp. 1-9. https://doi.org/10.1136/bmjopen-2016-015549
Communication intervention for autism spectrum disorders in minimally verbal children
Brignell, A., Song, H., Zhu, J., Suo, C., Lu, D. and Morgan, A. T.. (2016). Communication intervention for autism spectrum disorders in minimally verbal children. Cochrane Database of Systematic Reviews. 2016(11), p. Article CD012324. https://doi.org/10.1002/14651858.CD012324
Diagnosing autism : Australian paediatric research network surveys
Randall, Melinda, Albein-Urios, Natalia, Brignell, Amanda, Gulenc, Alisha, Hennel, Sabine, Coates, Cathy, Symeonides, Christos, Hiscock, Harriet, Marraffa, Catherine, Silove, Natalie, Bayl, Vivian, Woolfenden, Susan and Williams, Katrina. (2016). Diagnosing autism : Australian paediatric research network surveys. Journal of Paediatrics and Child Health. 52(1), pp. 11-17. https://doi.org/10.1111/jpc.13029
Regression in autism spectrum disorders
Williams, Katrina, Brignell, Amanda, Prior, Margot, Bartak, Lawrence and Roberts, Jacqueline. (2015). Regression in autism spectrum disorders. Journal of Paediatrics and Child Health. 51(1), pp. 61-64. https://doi.org/10.1111/jpc.12805
How relevant is the framework being used with autism spectrum disorders today?
Amanda Brignell, Angela Morgan, Susan Woolfenden and Katrina Williams. (2014). How relevant is the framework being used with autism spectrum disorders today? International Journal of Speech-Language Pathology. 16(1), pp. 43-49. https://doi.org/10.3109/17549507.2013.861870
Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD)
Williams, Katrina, Brignell, Amanda, Randall, Melinda Joy, Silove, Natalie and Hazell, Philip. (2013). Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). The Cochrane Database of Systematic Reviews. 8, pp. 1 - 51. https://doi.org/10.1002/14651858.CD004677.pub3