神经元连接蛋白36在肌萎缩侧索硬化症发病机制中的潜在作用。
A potential role for neuronal connexin 36 in the pathogenesis of amyotrophic lateral sclerosis.
作者信息
Belousov Andrei B, Nishimune Hiroshi, Denisova Janna V, Fontes Joseph D
机构信息
Departments of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
Departments of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
出版信息
Neurosci Lett. 2018 Feb 14;666:1-4. doi: 10.1016/j.neulet.2017.12.027. Epub 2017 Dec 12.
Abstract
Neuronal gap junctional protein connexin 36 (Cx36) contributes to neuronal death following a range of acute brain insults such as ischemia, traumatic brain injury and epilepsy. Whether Cx36 contributes to neuronal death and pathological outcomes in chronic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), is not known. We show here that the expression of Cx36 is significantly decreased in lumbar segments of the spinal cord of both human ALS subjects and SOD1 mice as compared to healthy human and wild-type mouse controls, respectively. In purified neuronal cultures prepared from the spinal cord of wild-type mice, knockdown of Cx36 reduces neuronal death caused by overexpression of the mutant human SOD1-G93A protein. Taken together, these data suggest a possible contribution of Cx36 to ALS pathogenesis. A perspective for the use of blockers of Cx36 gap junction channels for ALS therapy is discussed.
摘要
神经元间隙连接蛋白连接蛋白36（Cx36）在一系列急性脑损伤（如缺血、创伤性脑损伤和癫痫）后会导致神经元死亡。目前尚不清楚Cx36是否会导致慢性神经退行性疾病（如肌萎缩侧索硬化症，ALS）中的神经元死亡和病理结果。我们在此表明，与健康人类和野生型小鼠对照相比，人类ALS患者和SOD1小鼠脊髓腰段中Cx36的表达分别显著降低。在从野生型小鼠脊髓制备的纯化神经元培养物中，敲低Cx36可减少由突变型人类SOD1 - G93A蛋白过表达引起的神经元死亡。综上所述，这些数据表明Cx36可能对ALS发病机制有影响。本文还讨论了使用Cx36间隙连接通道阻滞剂治疗ALS的前景。
相似文献
1
A potential role for neuronal connexin 36 in the pathogenesis of amyotrophic lateral sclerosis.神经元连接蛋白36在肌萎缩侧索硬化症发病机制中的潜在作用。
Neurosci Lett. 2018 Feb 14;666:1-4. doi: 10.1016/j.neulet.2017.12.027. Epub 2017 Dec 12.
2
In-vivo effects of knocking-down metabotropic glutamate receptor 5 in the SOD1 mouse model of amyotrophic lateral sclerosis.在肌萎缩侧索硬化症的SOD1小鼠模型中敲除代谢型谷氨酸受体5的体内效应。
Neuropharmacology. 2017 Sep 1;123:433-445. doi: 10.1016/j.neuropharm.2017.06.020. Epub 2017 Jun 21.
3
The Overexpression of TDP-43 Protein in the Neuron and Oligodendrocyte Cells Causes the Progressive Motor Neuron Degeneration in the SOD1 G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.在超氧化物歧化酶1（SOD1）G93A转基因肌萎缩侧索硬化小鼠模型中，神经元和少突胶质细胞中TDP - 43蛋白的过表达导致进行性运动神经元变性。
Int J Biol Sci. 2016 Aug 15;12(9):1140-9. doi: 10.7150/ijbs.15938. eCollection 2016.
4
Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.敲除代谢型谷氨酸受体 1 可改善肌萎缩侧索硬化症 SOD1(G93A)小鼠模型的生存和疾病进展。
Neurobiol Dis. 2014 Apr;64:48-59. doi: 10.1016/j.nbd.2013.11.006. Epub 2013 Dec 19.
5
Death of Neurons following Injury Requires Conductive Neuronal Gap Junction Channels but Not a Specific Connexin.神经元损伤后的死亡需要传导性神经元间隙连接通道，但不需要特定的连接蛋白。
PLoS One. 2015 May 27;10(5):e0125395. doi: 10.1371/journal.pone.0125395. eCollection 2015.
6
Voltage-gated calcium channels are abnormal in cultured spinal motoneurons in the G93A-SOD1 transgenic mouse model of ALS.在肌萎缩侧索硬化症（ALS）的G93A-SOD1转基因小鼠模型中，培养的脊髓运动神经元中的电压门控钙通道异常。
Neurobiol Dis. 2016 Sep;93:78-95. doi: 10.1016/j.nbd.2016.04.009. Epub 2016 May 2.
7
Connexin 43 in astrocytes contributes to motor neuron toxicity in amyotrophic lateral sclerosis.星形胶质细胞中的连接蛋白43促成肌萎缩侧索硬化症中的运动神经元毒性。
Glia. 2016 Jul;64(7):1154-69. doi: 10.1002/glia.22989. Epub 2016 Apr 16.
8
Toll-Like Receptor-4 Inhibitor TAK-242 Attenuates Motor Dysfunction and Spinal Cord Pathology in an Amyotrophic Lateral Sclerosis Mouse Model.Toll样受体4抑制剂TAK-242减轻肌萎缩侧索硬化小鼠模型中的运动功能障碍和脊髓病理变化。
Int J Mol Sci. 2017 Aug 1;18(8):1666. doi: 10.3390/ijms18081666.
9
Immunogold evidence that neuronal gap junctions in adult rat brain and spinal cord contain connexin-36 but not connexin-32 or connexin-43.免疫金标证据表明，成年大鼠脑和脊髓中的神经元间隙连接含有连接蛋白-36，但不含有连接蛋白-32或连接蛋白-43。
Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7573-8. doi: 10.1073/pnas.97.13.7573.
10
GAB(A) receptors present higher affinity and modified subunit composition in spinal motor neurons from a genetic model of amyotrophic lateral sclerosis.在肌萎缩侧索硬化症基因模型的脊髓运动神经元中，GAB(A)受体表现出更高的亲和力和修饰的亚基组成。
Eur J Neurosci. 2008 Oct;28(7):1275-85. doi: 10.1111/j.1460-9568.2008.06436.x.
引用本文的文献
1
Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer.甲氟喹诱导 Cx36 N 端螺旋构象改变导致脂质双层介导的通道关闭。
Nat Commun. 2024 Oct 25;15(1):9223. doi: 10.1038/s41467-024-53587-6.
2
Astroglial connexin 43 is a novel therapeutic target for chronic multiple sclerosis model.星形胶质细胞连接蛋白 43 是慢性多发性硬化症模型的一个新的治疗靶点。
Sci Rep. 2024 May 13;14(1):10877. doi: 10.1038/s41598-024-61508-2.
3
Cryo-EM structures of human Cx36/GJD2 neuronal gap junction channel.人源 Cx36/GJD2 神经元缝隙连接通道的冷冻电镜结构。
Nat Commun. 2023 Mar 11;14(1):1347. doi: 10.1038/s41467-023-37040-8.
4
Connexin 30 Deficiency Ameliorates Disease Progression at the Early Phase in a Mouse Model of Amyotrophic Lateral Sclerosis by Suppressing Glial Inflammation.缝隙连接蛋白 30 缺乏通过抑制神经胶质炎症改善肌萎缩侧索硬化症小鼠模型的早期疾病进展。
Int J Mol Sci. 2022 Dec 16;23(24):16046. doi: 10.3390/ijms232416046.
5
Asymmetric Dimethylarginine Protects Neurons from Oxygen Glucose Deprivation Insult by Modulating Connexin-36 Expression.不对称二甲基精氨酸通过调节连接蛋白 36 的表达来保护神经元免受氧葡萄糖剥夺损伤。
Oxid Med Cell Longev. 2022 Jul 6;2022:5339361. doi: 10.1155/2022/5339361. eCollection 2022.
6
Altered Expression of Glial Gap Junction Proteins Cx43, Cx30, and Cx47 in the 5XFAD Model of Alzheimer's Disease.阿尔茨海默病5XFAD模型中胶质细胞间隙连接蛋白Cx43、Cx30和Cx47的表达改变
Front Neurosci. 2020 Oct 7;14:582934. doi: 10.3389/fnins.2020.582934. eCollection 2020.
7
Connexins-Based Hemichannels/Channels and Their Relationship with Inflammation, Seizures and Epilepsy.缝隙连接蛋白通道及其与炎症、癫痫发作和癫痫的关系。
Int J Mol Sci. 2019 Nov 27;20(23):5976. doi: 10.3390/ijms20235976.
8
Downregulation of Neuronal and Dendritic Connexin36-Made Electrical Synapses Without Glutamatergic Axon Terminals in Spinal Anterior Horn Cells From the Early Stage of Amyotrophic Lateral Sclerosis.肌萎缩侧索硬化症早期脊髓前角细胞中无谷氨酸能轴突终末的神经元和树突状连接蛋白36形成的电突触下调
Front Neurosci. 2018 Nov 28;12:894. doi: 10.3389/fnins.2018.00894. eCollection 2018.
9
Cues to Opening Mechanisms From Electric Field Excitation of Cx26 Hemichannel and Mutagenesis Studies in HeLa Transfectans.来自Cx26半通道电场激发及HeLa转染细胞诱变研究对开放机制的提示
Front Mol Neurosci. 2018 May 31;11:170. doi: 10.3389/fnmol.2018.00170. eCollection 2018.
本文引用的文献
1
Death of Neurons following Injury Requires Conductive Neuronal Gap Junction Channels but Not a Specific Connexin.神经元损伤后的死亡需要传导性神经元间隙连接通道，但不需要特定的连接蛋白。
PLoS One. 2015 May 27;10(5):e0125395. doi: 10.1371/journal.pone.0125395. eCollection 2015.
2
NAP (davunetide) modifies disease progression in a mouse model of severe neurodegeneration: protection against impairments in axonal transport.NAP（达文肽）可改变严重神经退行性变小鼠模型中的疾病进展：防止轴突运输损伤。
Neurobiol Dis. 2013 Aug;56:79-94. doi: 10.1016/j.nbd.2013.04.012. Epub 2013 Apr 28.
3
Enhancing mitochondrial calcium buffering capacity reduces aggregation of misfolded SOD1 and motor neuron cell death without extending survival in mouse models of inherited amyotrophic lateral sclerosis.增强线粒体钙缓冲能力可减少错误折叠的 SOD1 聚集和运动神经元死亡，但不能延长遗传性肌萎缩侧索硬化症小鼠模型的生存期。
J Neurosci. 2013 Mar 13;33(11):4657-71. doi: 10.1523/JNEUROSCI.1119-12.2013.
4
Neuronal gap junctions: making and breaking connections during development and injury.神经元缝隙连接：在发育和损伤过程中建立和断开连接。
Trends Neurosci. 2013 Apr;36(4):227-36. doi: 10.1016/j.tins.2012.11.001. Epub 2012 Dec 11.
5
Mutant SOD1G93A triggers mitochondrial fragmentation in spinal cord motor neurons: neuroprotection by SIRT3 and PGC-1α.突变型 SOD1G93A 触发脊髓运动神经元中线粒体片段化：SIRT3 和 PGC-1α 的神经保护作用。
Neurobiol Dis. 2013 Mar;51:72-81. doi: 10.1016/j.nbd.2012.07.004. Epub 2012 Jul 20.
6
Neuronal gap junctions play a role in the secondary neuronal death following controlled cortical impact.神经元缝隙连接在皮质撞击伤后继发性神经元死亡中起作用。
Neurosci Lett. 2012 Aug 22;524(1):16-9. doi: 10.1016/j.neulet.2012.06.065. Epub 2012 Jul 7.
7
Neuronal gap junction coupling is regulated by glutamate and plays critical role in cell death during neuronal injury.神经元缝隙连接偶联受谷氨酸调节，在神经元损伤过程中的细胞死亡中发挥关键作用。
J Neurosci. 2012 Jan 11;32(2):713-25. doi: 10.1523/JNEUROSCI.3872-11.2012.
8
Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease.缝隙连接半通道阻断抑制肌萎缩侧索硬化症和阿尔茨海默病小鼠模型的疾病进展。
PLoS One. 2011;6(6):e21108. doi: 10.1371/journal.pone.0021108. Epub 2011 Jun 21.
9
Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis.用 Trichostatin A 治疗疾病发作后，可延迟肌萎缩性侧索硬化症小鼠模型的疾病进展并提高存活率。
Exp Neurol. 2011 Sep;231(1):147-59. doi: 10.1016/j.expneurol.2011.06.003. Epub 2011 Jun 25.
10
Interplay of chemical neurotransmitters regulates developmental increase in electrical synapses.化学神经递质的相互作用调节电突触的发育性增加。
J Neurosci. 2011 Apr 20;31(16):5909-20. doi: 10.1523/JNEUROSCI.6787-10.2011.
Zotero 插件