Journal Club (October 15, 2019)

本日は、mRNAの品質管理異常に起因する免疫応答の活性化が行動的・電気生理学的異常を引き起こす論文について勉強しました。

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

Jennifer L.Johnson1227LoredanaStoica2327YuweiLiu1227Ping JunZhu12AbhisekBhattacharya45Shelly A.Buffington12RedwanHuq6N. TonyEissa45OlaLarsson7Bo T.Porse8910DeeptiDomingo11UrwahNawaz12ReneeCarroll12LachlanJolly12Tom S.Scerri13Hyung-GooKim14AmandaBrignell15Matthew J.Coleman16MauroCosta-Mattioli12328

Neuron. 2019 Oct 1. pii: S0896-6273(19)30733-0. doi: 10.1016/j.neuron.2019.08.027. [Epub ahead of print]

Highlights
• Humans carrying novel variants in UPF2 exhibit speech and language deficits

• Upf2-deficient mice and flies have impaired NMD and exhibit behavioral deficits

• Inhibition of Upf2-dependent NMD triggers immune activation in mice

• Reduction of brain inflammation reverses synaptic and behavioral deficits

Summary

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.

https://www.sciencedirect.com/science/article/pii/S0896627319307330?via%3Dihub

論文紹介:ST

AI (Artificial Intelligence) and communication network concept.

コメントを残す

メールアドレスが公開されることはありません。 が付いている欄は必須項目です

このサイトはスパムを低減するために Akismet を使っています。コメントデータの処理方法の詳細はこちらをご覧ください