FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization.
FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization.
复制标题
DOI：
10.1038/ncomms8098
复制
发表时间：
2015-05-13
影响因子：
16.6
通讯作者：
Sobue, Gen
中科院分区：
文献类型：
--
作者：
Udagawa, Tsuyoshi;Fujioka, Yusuke;Tanaka, Motoki;Honda, Daiyu;Yokoi, Satoshi;Riku, Yuichi;Ibi, Daisuke;Nagai, Taku;Yamada, Kiyofumi;Watanabe, Hirohisa;Katsuno, Masahisa;Inada, Toshifumi;Ohno, Kinji;Sokabe, Masahiro;Okado, Haruo;Ishigaki, Shinsuke;Sobue, Gen
FUS是一种RNA/DNA结合蛋白，参与基因表达的多个步骤，与肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）相关。然而，FUS介导的特定致病和/或修饰机制在很大程度上是未知的。在这里，我们评估FUS对突触功能和动物行为的内在作用。我们发现，FUS耗竭下调GluA 1，AMPA受体的亚基。FUS在3′端附近结合GluA 1 mRNA，并控制poly（A）尾的维持，从而调节稳定性。GluA 1减少FUS敲低降低微型EPSC振幅在培养的神经元和在体内。海马FUS敲低可减弱树突棘成熟，并导致行为异常，包括多动、去抑制和社会互动缺陷，这些可通过GluA 1重新引入而部分改善。这些结果突出了FUS在调节GluA 1 mRNA稳定性、突触后功能和FTLD样动物行为中的关键作用。 FUS是一种RNA/DNA结合蛋白，参与基因表达调控，与肌萎缩侧索硬化和额颞叶痴呆（FTLD）有关，但致病机制尚不清楚。在这里，作者表明FUS调节GluA 1 mRNA和树突成熟的稳定性，并在FTLD相关行为中发挥作用。
FUS is an RNA/DNA-binding protein involved in multiple steps of gene expression and is associated with amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). However, the specific disease-causing and/or modifying mechanism mediated by FUS is largely unknown. Here we evaluate intrinsic roles of FUS on synaptic functions and animal behaviours. We find that FUS depletion downregulates GluA1, a subunit of AMPA receptor. FUS binds GluA1 mRNA in the vicinity of the 3′ terminus and controls poly (A) tail maintenance, thus regulating stability. GluA1 reduction upon FUS knockdown reduces miniature EPSC amplitude both in cultured neurons and in vivo. FUS knockdown in hippocampus attenuates dendritic spine maturation and causes behavioural aberrations including hyperactivity, disinhibition and social interaction defects, which are partly ameliorated by GluA1 reintroduction. These results highlight the pivotal role of FUS in regulating GluA1 mRNA stability, post-synaptic function and FTLD-like animal behaviours. FUS is an RNA/DNA-binding protein involved in gene expression regulation and associated with amyotrophic lateral sclerosis and frontotemporal dementia (FTLD) but the disease-causing mechanisms are unclear. Here the authors show that FUS regulates the stability of GluA1 mRNA and dendritic maturation and plays a role in FTLD-associated behaviours.
登录
查看更多内容
影响因子：
11.2
作者：
Noro, T;Miyake, K;Shimada, T
通讯作者：
Shimada, T
影响因子：
14.9
作者：
La Via L;Bonini D;Russo I;Orlandi C;Barlati S;Barbon A
通讯作者：
Barbon A
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
DOI：
10.1007/978-1-59745-248-9_9
发表时间：
2011-01-01
期刊：
RNA: METHODS AND PROTOCOLS
影响因子：
--
作者：
Meijer, Hedda A.;de Moor, Cornelia H.
通讯作者：
de Moor, Cornelia H.
影响因子：
14.5
作者：
Hornberger, Michael;Wong, Stephanie;Halliday, Glenda
通讯作者：
Halliday, Glenda