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

Date

2019

Authors

Johnson, J.L.
Stoica, L.
Liu, Y.
Zhu, P.J.
Bhattacharya, A.
Buffington, S.
Huq, R.
Eissa, N.T.
Larsson, O.
Porse, B.T.

Editors

Advisors

Journal Title

Journal ISSN

Volume Title

Type:

Journal article

Citation

Neuron, 2019; 104(4):665-679.e8

Statement of Responsibility

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, and Mauro Costa-Mattioli

Conference Name

DOI

10.1016/j.neuron.2019.08.027

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.

School/Discipline

Dissertation Note

Provenance

Description

Access Status

Rights

© 2019 Published by Elsevier Inc.

License

Grant ID

http://purl.org/au-research/grants/nhmrc/1155224
 http://purl.org/au-research/grants/nhmrc/1091593
 http://purl.org/au-research/grants/arc/DE160100620
 http://purl.org/au-research/grants/nhmrc/1116976
 http://purl.org/au-research/grants/nhmrc/1127144
 http://purl.org/au-research/grants/nhmrc/1105008
 http://purl.org/au-research/grants/nhmrc/1063799
 http://purl.org/au-research/grants/nhmrc/1006110
 http://purl.org/au-research/grants/nhmrc/1102971

Published Version

https://doi.org/10.1016/j.neuron.2019.08.027

Call number

Persistent link to this record

http://hdl.handle.net/2440/122742