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

Jennifer L Johnson; Loredana Stoica; Yuwei Liu; Ping Jun Zhu; Abhisek Bhattacharya; Shelly 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

doi:10.1016/j.neuron.2019.08.027

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

Jennifer L Johnson, Loredana Stoica, Yuwei Liu, Ping Jun Zhu, Abhisek Bhattacharya, Shelly 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 KiniVictoria 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

Department of Clinical Medicine

11 Citations (Scopus)

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.

Original language	English
Journal	Neuron
ISSN	0896-6273
DOIs	https://doi.org/10.1016/j.neuron.2019.08.027
Publication status	Published - 20 Nov 2019

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Johnson, J. L., Stoica, L., Liu, Y., Zhu, P. J., Bhattacharya, A., Buffington, S., Huq, R., Eissa, N. T., Larsson, O., Porse, B. T., Domingo, D., Nawaz, U., Carroll, R., Jolly, L., Scerri, T. S., Kim, H-G., Brignell, A., Coleman, M. J., Braden, R., ... Costa-Mattioli, M. (2019). Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response. Neuron. https://doi.org/10.1016/j.neuron.2019.08.027

Johnson, JL, Stoica, L, Liu, Y, Zhu, PJ, Bhattacharya, A, Buffington, S, Huq, R, Eissa, NT, Larsson, O, Porse, BT, Domingo, D, Nawaz, U, Carroll, R, Jolly, L, Scerri, TS, Kim, H-G, Brignell, A, Coleman, MJ, Braden, R, Kini, U, Jackson, V, Baxter, A, Bahlo, M, Scheffer, IE, Amor, DJ, Hildebrand, MS, Bonnen, PE, Beeton, C, Gecz, J, Morgan, AT & Costa-Mattioli, M 2019, 'Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response', Neuron. https://doi.org/10.1016/j.neuron.2019.08.027

@article{5f7abb3036a6495abe6e42dcf50f7331,

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

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.",

author = "Johnson, {Jennifer L} and Loredana Stoica and Yuwei Liu and Zhu, {Ping Jun} and Abhisek Bhattacharya and Shelly Buffington and Redwan Huq and Eissa, {N Tony} and Ola Larsson and Porse, {Bo T} and Deepti Domingo and Urwah Nawaz and Renee Carroll and Lachlan Jolly and Scerri, {Tom S} and Hyung-Goo Kim and Amanda Brignell and Coleman, {Matthew J} and Ruth Braden and Usha Kini and Victoria Jackson and Anne Baxter and Melanie Bahlo and Scheffer, {Ingrid E} and Amor, {David J} and Hildebrand, {Michael S} and Bonnen, {Penelope E} and Christine Beeton and Jozef Gecz and Morgan, {Angela T} and Mauro Costa-Mattioli",

note = "Copyright {\textcopyright} 2019. Published by Elsevier Inc.",

year = "2019",

month = nov,

day = "20",

doi = "10.1016/j.neuron.2019.08.027",

language = "English",

journal = "Neuron",

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T1 - Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response

AU - Johnson, Jennifer L

AU - Stoica, Loredana

AU - Liu, Yuwei

AU - Zhu, Ping Jun

AU - Bhattacharya, Abhisek

AU - Buffington, Shelly

AU - Huq, Redwan

AU - Eissa, N Tony

AU - Larsson, Ola

AU - Porse, Bo T

AU - Domingo, Deepti

AU - Nawaz, Urwah

AU - Carroll, Renee

AU - Jolly, Lachlan

AU - Scerri, Tom S

AU - Kim, Hyung-Goo

AU - Brignell, Amanda

AU - Coleman, Matthew J

AU - Braden, Ruth

AU - Kini, Usha

AU - Jackson, Victoria

AU - Baxter, Anne

AU - Bahlo, Melanie

AU - Scheffer, Ingrid E

AU - Amor, David J

AU - Hildebrand, Michael S

AU - Bonnen, Penelope E

AU - Beeton, Christine

AU - Gecz, Jozef

AU - Morgan, Angela T

AU - Costa-Mattioli, Mauro

PY - 2019/11/20

Y1 - 2019/11/20

N2 - 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.

AB - 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.

U2 - 10.1016/j.neuron.2019.08.027

DO - 10.1016/j.neuron.2019.08.027

M3 - Journal article

C2 - 31585809

SN - 0896-6273

JO - Neuron

JF - Neuron

ER -

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

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