Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability.
Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability.
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DOI：
10.1111/jnc.14553
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发表时间：
2018-11
影响因子：
4.7
通讯作者：
Ikenaka K
中科院分区：
文献类型：
--
作者：
Kunisawa K;Shimizu T;Kushima I;Aleksic B;Mori D;Osanai Y;Kobayashi K;Taylor AM;Bhat MA;Hayashi A;Baba H;Ozaki N;Ikenaka K
有髓轴突将轴索膜分成四个区域：Ranvier结节、旁阳极、旁阳极和节间。结旁连接由特定的组成蛋白组成，如神经胶质细胞侧的Neuroseon155(NF155)，轴突侧的CASPR和Contactin。虽然结旁连接被认为在快速跳跃传导和结节组装中起着关键作用，但它们与神经元相互作用的作用并不完全清楚。在先前的一项研究中，少突胶质细胞的条件性NF155基因敲除导致了结旁连接的解体。为了检测结旁连接的中断是否影响神经元基因的表达，我们从NF155条件性基因敲除的视网膜提取总RNA，并进行表达分析。我们发现433个基因的表达水平随着旁结节消融的反应而改变。有趣的是，水通道蛋白3(AQP3)的表达在NF155条件性基因敲除小鼠中显著减少，但在脑苷硫基转移酶基因敲除小鼠(CST-KO)中却没有，因为CST-KO小鼠在发育过程中最初不形成偏阳极。拷贝数变异(CNV)在精神分裂症(SCZ)的病因学中具有重要作用。我们在SCZ患者中观察到罕见的AQP3重复，提示AQP3的异常表达与SCZ有关。为了确定AQP3在NF155条件性基因敲除小鼠中的过表达是否影响神经功能，我们对腺相关病毒(AAV)介导的AQP3在小鼠运动皮质中的过表达进行了研究，发现在AQP3转导的细胞中，依赖于caspase-3的神经细胞凋亡显著增加。这项研究可能通过调节AQP3的表达为SCZ的治疗方法提供新的见解，AQP3与结旁路中断相关。水通道蛋白3与精神分裂症拷贝数变异相关的基因，提示水通道蛋白3的异常表达与精神分裂症有关。我们发现水通道蛋白3对旁结节异常敏感。我们进一步表明，通过破坏旁阳极而导致水通道蛋白3表达失调影响了神经元的存活率。进一步了解水通道蛋白3的功能可能会为少突胶质细胞异常引起的精神分裂症的病因和潜在的治疗方法提供新的见解。
Myelinated axons segregate the axonal membrane into four defined regions: the node of Ranvier, paranode, juxtaparanode and internode. The paranodal junction consists of specific component proteins, such as neurofascin155 (NF155) on the glial side, and Caspr and Contactin on the axonal side. Although paranodal junctions are thought to play crucial roles in rapid saltatory conduction and nodal assembly, the role of their interaction with neurons is not fully understood. In a previous study, conditional NF155 knockout in oligodendrocytes led to disorganization of the paranodal junctions. To examine if disruption of paranodal junctions affects neuronal gene expression, we prepared total RNA from the retina of NF155 conditional knockout, and performed expression analysis. We found that the expression level of 433 genes changed in response to paranodal junction ablation. Interestingly, expression of aquaporin 3 (AQP3) was significantly reduced in NF155 conditional knockout mice, but not in cerebroside sulfotransferase knockout (CST-KO) mice, whose paranodes are not originally formed during development. Copy number variations (CNVs) have an important role in the etiology of schizophrenia (SCZ). We observed rare duplications of AQP3 in SCZ patients, suggesting a correlation between abnormal AQP3 expression and SCZ. To determine if AQP3 overexpression in NF155 conditional knockout mice influences neuronal function, we performed adeno-associated virus (AAV)-mediated overexpression of AQP3 in the motor cortex of mice and found a significant increase in caspase-3-dependent neuronal apoptosis in AQP3-transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP3 expression, which is associated with paranodal disruption. The aquaporin 3 was related to the list of genes identified with copy number variations of schizophrenia, suggesting a correlation between abnormal aquaporin 3 expression and schizophrenia. We found that aquaporin 3 was sensitive to paranodal abnormalities. We further showed that dysregulation of aquaporin 3 expression through disruption of paranode affected neuronal viability. Further understanding of aquaporin 3 function may provide new insights into the etiology of schizophrenia caused by oligodendrocyte abnormalities and potential therapeutic approaches.
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影响因子：
4.8
作者：
Iozzo, Renato V.;Buraschi, Simone;Morrione, Andrea
通讯作者：
Morrione, Andrea
影响因子：
5.3
作者：
Liu, Jia;Dupree, Jeffrey L.;Casaccia, Patrizia
通讯作者：
Casaccia, Patrizia
影响因子：
1.5
作者：
Doerflinger, NH;Macklin, WB;Popko, B
通讯作者：
Popko, B
DOI：
10.1038/nrneurol.2015.15
发表时间：
2015-03-01
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Malkki, Hemi
通讯作者：
Malkki, Hemi
影响因子：
5.7
作者：
Holm A;Magnusson KE;Vikström E
通讯作者：
Vikström E