Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects.
Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects.
复制标题
细胞质FUS触发与皮质神经元过度活跃和抑制性突触缺陷相关的早期行为改变。
DOI：
10.1038/s41467-021-23187-9
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发表时间：
2021-05-21
影响因子：
16.6
通讯作者：
Dupuis L
中科院分区：
文献类型：
--
作者：
Scekic-Zahirovic J;Sanjuan-Ruiz I;Kan V;Megat S;De Rossi P;Dieterlé S;Cassel R;Jamet M;Kessler P;Wiesner D;Tzeplaeff L;Demais V;Sahadevan S;Hembach KM;Muller HP;Picchiarelli G;Mishra N;Antonucci S;Dirrig-Grosch S;Kassubek J;Rasche V;Ludolph A;Boutillier AL;Roselli F;Polymenidou M;Lagier-Tourenne C;Liebscher S;Dupuis L
基因突变导致RNA结合蛋白FUS的细胞质错误定位，导致严重形式的肌萎缩侧索硬化症（ALS）。在其他疾病中也观察到FUS的细胞质蓄积，后果未知。在这里，我们表明，细胞质中的FUS错误定位驱动的行为异常，在敲入小鼠，包括运动过度活跃和改变社会交往，在没有广泛的神经元损失。从机制上讲，我们确定了Fus基因敲入小鼠体内额叶皮层神经元活动的逐步增加，与突触基因表达的改变有关。突触超微结构和形态缺陷在抑制性突触中比兴奋性突触更明显，并且与FUS及其RNA靶点的突触体水平增加相关。因此，细胞质FUS触发突触缺陷，这导致额叶皮层中神经元活动增加并引起相关的行为表型。这些结果表明，FUS错误定位可能引发ALS中运动神经元损伤以外的有害表型，可能也与以FUS错误定位为特征的其他神经退行性疾病相关。RNA结合蛋白FUS的突变与ALS相关。在这里，作者表明，在FUS基因敲入小鼠中，额叶皮层的神经元活动逐渐增加，这与突触基因表达的改变有关。
Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a progressive increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo, associated with altered synaptic gene expression. Synaptic ultrastructural and morphological defects were more pronounced in inhibitory than excitatory synapses and associated with increased synaptosomal levels of FUS and its RNA targets. Thus, cytoplasmic FUS triggers synaptic deficits, which is leading to increased neuronal activity in frontal cortex and causing related behavioral phenotypes. These results indicate that FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, likely relevant also for other neurodegenerative diseases characterized by FUS mislocalization. Mutations in the RNA binding protein FUS are associated with ALS. Here the authors show that in FUS knock-in mice there is a progressive increase in neuronal activity in the frontal cortex which is associated with altered synaptic gene expression.
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DOI：
10.1124/jpet.106.104406
发表时间：
2006-10-01
影响因子：
3.5
作者：
Borghese, C. M.;Werner, D. F.;Harrison, N. L.
通讯作者：
Harrison, N. L.
影响因子：
7.7
作者：
Dorgans, Kevin;Demais, Valerie;Doussau, Frederic
通讯作者：
Doussau, Frederic
DOI：
10.1080/21678421.2020.1733021
发表时间：
2020-02-28
影响因子：
2.8
作者：
Flies, C. M.;Veldink, J. H.
通讯作者：
Veldink, J. H.
DOI：
10.1016/s0140-6736(15)00461-4
发表时间：
2015-10-24
期刊：
Lancet (London, England)
影响因子：
--
作者：
Bang J;Spina S;Miller BL
通讯作者：
Miller BL
影响因子：
5.3
作者：
Clark, Rosemary M.;Brizuela, Mariana;Dickson, Tracey C.
通讯作者：
Dickson, Tracey C.