The small GTPase Arf6 is dysregulated in a mouse model for fragile X syndrome
The small GTPase Arf6 is dysregulated in a mouse model for fragile X syndrome
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DOI：
10.1111/jnc.15230
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发表时间：
2020-12-12
影响因子：
4.7
通讯作者：
Kornau, Hans-Christian
中科院分区：
文献类型：
--
作者：
Brisevac, Dusica;Scholz, Raif;Kornau, Hans-Christian
脆性X综合征（FXS）是智力残疾的最常见遗传原因，由脆性X智力低下基因1（FMR 1）沉默引起。对FXS患者的脑尸检分析显示，皮质区未成熟树突棘的密度增加。我们推测，小GTd 6 Arf 6，肌动蛋白调节器的发展至关重要的神经元突触和树突棘，是牵连在FXS。在这里，我们确定了部分的活性，GTP结合的Arf 6在皮层神经元培养和突触神经小体从Fmr 1基因敲除小鼠，肌动蛋白聚合的神经元表达Arf 6突变体与变体GTP或GDP结合特性，并记录海马长期抑郁症引起的代谢型谷氨酸受体（mGluR-LTD）在急性脑切片。我们检测到持续升高的Arf 6活性，Arf 6对突触刺激的敏感性丧失，以及成熟的Fmr 1敲除神经元中Arf 6依赖的树突状肌动蛋白聚合增加。在野生型神经元中，通过RNAi介导的突触后Arf 6鸟苷酸交换因子IQSEC 1（BRAG 2）或IQSEC 2（BRAG 1）的耗竭，导致Arf 6-GTP水平和肌动蛋白丝组装的类似失衡。3周龄小鼠海马神经元中Iqsec 1的靶向缺失干扰野生型mGluR-LTD，但不在Fmr 1敲除小鼠中。总的来说，这些数据表明，在Fmr 1敲除神经元的肌动蛋白细胞骨架，脊柱形态和突触可塑性的后果异常Arf 6调节。此外，FXS和IQSEC 1和IQSEC 2中的遗传变异引起的综合征共享智力残疾和发育迟缓作为主要症状。因此，Arf 6的失调可能有助于FXS中的认知损害。
Fragile X syndrome (FXS), the most common inherited cause of intellectual disability, results from silencing of the fragile X mental retardation gene 1 (FMR1). The analyses of FXS patients' brain autopsies revealed an increased density of immature dendritic spines in cortical areas. We hypothesize that the small GTPase Arf6, an actin regulator critical for the development of glutamatergic synapses and dendritic spines, is implicated in FXS. Here, we determined the fraction of active, GTP-bound Arf6 in cortical neuron cultures and synaptoneurosomes from Fmr1 knockout mice, measured actin polymerization in neurons expressing Arf6 mutants with variant GTP- or GDP-binding properties, and recorded hippocampal long-term depression induced by metabotropic glutamate receptors (mGluR-LTD) in acute brain slices. We detected a persistently elevated Arf6 activity, a loss of Arf6 sensitivity to synaptic stimulation and an increased Arf6-dependent dendritic actin polymerization in mature Fmr1 knockout neurons. Similar imbalances in Arf6-GTP levels and actin filament assembly were caused in wild-type neurons by RNAi-mediated depletion of the postsynaptic Arf6 guanylate exchange factors IQSEC1 (BRAG2) or IQSEC2 (BRAG1). Targeted deletion of Iqsec1 in hippocampal neurons of 3-week-old mice interfered with mGluR-LTD in wild-type, but not in Fmr1 knockout mice. Collectively, these data suggest an aberrant Arf6 regulation in Fmr1 knockout neurons with consequences for the actin cytoskeleton, spine morphology, and synaptic plasticity. Moreover, FXS and syndromes caused by genetic variants in IQSEC1 and IQSEC2 share intellectual disabilities and developmental delay as main symptoms. Therefore, dysregulation of Arf6 may contribute to the cognitive impairment in FXS.