Extensive dysregulations of oligodendrocytic and astrocytic connexins are associated with disease progression in an amyotrophic lateral sclerosis mouse model.
Extensive dysregulations of oligodendrocytic and astrocytic connexins are associated with disease progression in an amyotrophic lateral sclerosis mouse model.
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DOI：
10.1186/1742-2094-11-42
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发表时间：
2014-03-06
影响因子：
9.3
通讯作者：
Kira J
中科院分区：
文献类型：
--
作者：
Cui Y;Masaki K;Yamasaki R;Imamura S;Suzuki SO;Hayashi S;Sato S;Nagara Y;Kawamura MF;Kira J
在一个由突变型铜/锌超氧化物歧化酶1（mSOD1）介导的肌萎缩侧索硬化（ALS）模型中，提示存在非细胞自主性运动神经元死亡，其中神经胶质细胞在疾病进展中起重要作用。连接蛋白（Cxs）形成同型或异型缝隙连接（GJs），并允许神经组织细胞之间进行直接的细胞间通讯。Cxs在运动神经元疾病中的作用从未被研究过；因此，我们旨在评估mSOD1转基因（mSOD1 - Tg）小鼠与同龄的非转基因（非 - Tg）同窝小鼠相比，Cxs的变化。
我们从病理学角度评估了在症状前、疾病进展期和终末期，星形胶质细胞的Cx43/Cx30和少突胶质细胞的Cx47/Cx32免疫反应性相对于水通道蛋白 - 4（AQP4）、胶质纤维酸性蛋白（GFAP）、兴奋性氨基酸转运体 - 2（EAAT2）、髓鞘少突胶质细胞糖蛋白（MOG）和Nogo - A免疫反应性的时间变化，并通过NeuN和神经丝免疫染色观察神经元丢失，通过Iba - 1免疫染色观察小胶质细胞反应。我们还对Cxs进行了定量免疫印迹和实时PCR分析。
与非 - Tg小鼠相比，mSOD1 - Tg小鼠在疾病进展期和终末期，腰脊髓前角出现神经元和轴突丢失，同时小胶质细胞活化增加。在症状前阶段，mSOD1 - Tg小鼠和非 - Tg小鼠之间Cxs的表达模式没有差异，但在疾病进展期和终末期，mSOD1 - Tg小鼠前角的GFAP、Cx43、Cx30和AQP4免疫反应性增加。相比之下，在疾病进展期和终末期，mSOD1 - Tg小鼠前角的Nogo - A阳性少突胶质细胞中，Cx47和Cx32免疫反应性显著降低，特别是在显示SOD1积聚的少突胶质细胞中。在疾病进展期和终末期，mSOD1 - Tg小鼠前角的EAAT2免疫反应性也降低。定量免疫印迹显示，在疾病进展期和终末期，mSOD1 - Tg小鼠的Cx47和Cx32蛋白水平显著降低。在这些阶段，Cx47和Cx32的mRNA水平也降低。
我们的研究结果表明，在mSOD1 - Tg小鼠中，脊髓前角的少突胶质细胞和星形胶质细胞的缝隙连接蛋白在疾病进展期和终末期受到深刻影响，其中神经胶质细胞之间缝隙连接的破坏可能加剧运动神经元死亡。
Non-cell-autonomous motor neuronal death is suggested in a mutant Cu/Zn superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis (ALS) model, in which glial cells play significant roles in disease progression. Connexins (Cxs) form homotypic or heterotypic gap junctions (GJs) and allow direct intercellular communications among nervous tissue cells. The role of Cxs in motor neuron disease has never been investigated; therefore, we aimed to evaluate alterations of Cxs in mSOD1-transgenic (mSOD1-Tg) mice in comparison with their non-transgenic (non-Tg) littermates at the same ages. We pathologically evaluated temporal changes to astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 immunoreactivities at presymptomatic, disease-progressive, and end stages, relative to aquaporin-4 (AQP4), glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-2 (EAAT2), myelin-oligodendrocyte glycoprotein (MOG), and Nogo-A immunoreactivities, and observed neuronal loss by NeuN and neurofilament immunostaining, and microglial response by Iba-1 immunostaining. We also performed quantitative immunoblotting and real-time PCR analyses for Cxs. The mSOD1-Tg mice showed neuronal and axonal loss in the anterior horns of the lumbar spinal cord accompanied by increased activation of microglia compared with non-Tg mice at the disease-progressive and end stages. Expression patterns of Cxs were not different between mSOD1-Tg and non-Tg mice at the presymptomatic stage, but immunoreactivities for GFAP, Cx43, Cx30 and AQP4 were increased in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. By contrast, Cx47 and Cx32 immunoreactivities were markedly diminished in Nogo-A-positive oligodendrocytes in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages, especially in oligodendrocytes showing SOD1 accumulation. EAAT2 immunoreactivity was also diminished in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. Quantitative immunoblotting revealed a significant reduction in Cx47 and Cx32 protein levels in mSOD1-Tg mice at the disease-progressive and end stages. The levels of Cx47 and Cx32 mRNAs were also decreased at these stages. Our findings indicate that oligodendrocytic and astrocytic GJ proteins in the anterior horns of spinal cord in mSOD1-Tg mice are profoundly affected at the disease-progressive and end stages, where disruption of GJs among glial cells may exacerbate motor neuronal death.
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影响因子：
25
作者：
Kang, Shin H.;Li, Ying;Fukaya, Masahiro;Lorenzini, Ileana;Cleveland, Don W.;Ostrow, Lyle W.;Rothstein, Jeffrey D.;Bergles, Dwight E.
通讯作者：
Bergles, Dwight E.
影响因子：
3.3
作者：
Mei, X.;Ezan, P.;Koulakoff, A.
通讯作者：
Koulakoff, A.
影响因子：
5.3
作者：
Menichella, DM;Goodenough, DA;Paul, DL
通讯作者：
Paul, DL
影响因子：
4.7
作者：
Orellana JA;Froger N;Ezan P;Jiang JX;Bennett MV;Naus CC;Giaume C;Sáez JC
通讯作者：
Sáez JC
影响因子：
3.7
作者：
Masaki K;Suzuki SO;Matsushita T;Matsuoka T;Imamura S;Yamasaki R;Suzuki M;Suenaga T;Iwaki T;Kira J
通讯作者：
Kira J