The thrombin receptor modulates astroglia-neuron trophic coupling and neural repair after spinal cord injury.
The thrombin receptor modulates astroglia-neuron trophic coupling and neural repair after spinal cord injury.
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凝血酶受体调节脊髓损伤后星形胶质细胞-神经元营养偶联和神经修复。
DOI：
10.1002/glia.24012
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发表时间：
2021-09
期刊：
影响因子：
6.2
通讯作者：
Scarisbrick IA
中科院分区：
文献类型：
--
作者：
Kim HN;Triplet EM;Radulovic M;Bouchal S;Kleppe LS;Simon WL;Yoon H;Scarisbrick IA
凝血酶受体，蛋白酶激活受体1 （PAR1）的过度激活与从神经退行性疾病到神经创伤的多种神经病理有关。PAR1基因敲除小鼠在实验性脊髓损伤（SCI）后表现出改善的结果，然而，缺乏关于其基础细胞和分子机制的信息。在这里，我们证明了雌性小鼠PAR1的遗传阻断导致胸脊髓外侧压迫损伤后感觉运动协调的改善。我们发现，经过30天的恢复期后，突触素-1突触前蛋白和生长锥标记物GAP43的含量增加，神经元保存得到了改善。这些改善与髓鞘弹性和修复能力增强的迹象相结合，包括成熟少突胶质细胞及其祖细胞数量的增加和髓鞘碱性蛋白的丰度。这些神经恢复底物的显著增加伴随着星形胶质细胞（Serp1）和小胶质/单核细胞（CD68和iNOS）促炎标志物的减少，星形胶质细胞（S100A10和Emp1）和小胶质细胞（Arg1）标志物的协同增加，反映促修复活性。互补星形胶质细胞-神经元共培养生物测定表明，PAR1功能丧失的星形胶质细胞促进神经元存活和神经突生长。此外，通过抑制TrkB（脑源性神经营养因子的高亲和力受体），关闭星形胶质细胞PAR1的前神经突生长效应被阻断。总之，这些研究证明了PAR1在调节神经胶质-神经元相互作用中的独特调节作用，包括神经营养因子信号传导的能力，并强调了其在神经生物学交叉点的地位，这对于中枢神经系统对损伤的反应以及再生修复和功能恢复的能力至关重要。
Excessive activation of the thrombin receptor, Protease Activated Receptor 1 (PAR1) is implicated in diverse neuropathologies from neurodegenerative conditions to neurotrauma. PAR1 knockout mice show improved outcomes after experimental spinal cord injury (SCI), however, information regarding the underpinning cellular and molecular mechanisms is lacking. Here we demonstrate that genetic blockade of PAR1 in female mice results in improvements in sensorimotor co-ordination after thoracic spinal cord lateral compression injury. We document improved neuron preservation with increases in Synapsin-1 pre-synaptic proteins and GAP43, a growth cone marker, after a 30 d recovery period. These improvements were coupled to signs of enhanced myelin resiliency and repair, including increases in the number of mature oligodendrocytes, their progenitors and the abundance of myelin basic protein. These significant increases in substrates for neural recovery were accompanied by reduced astrocyte (Serp1) and microglial/monocyte (CD68 and iNOS) pro-inflammatory markers, with coordinate increases in astrocyte (S100A10 and Emp1) and microglial (Arg1) markers reflective of pro-repair activities. Complementary astrocyte-neuron co-culture bioassays suggest astrocytes with PAR1 loss-of-function promote both neuron survival and neurite outgrowth. Additionally, the pro-neurite outgrowth effects of switching off astrocyte PAR1 were blocked by inhibiting TrkB, the high affinity receptor for brain derived neurotrophic factor. Altogether, these studies demonstrate unique modulatory roles for PAR1 in regulating glial-neuron interactions, including the capacity for neurotrophic factor signaling, and underscore its position at neurobiological intersections critical for the response of the CNS to injury and the capacity for regenerative repair and restoration of function.
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影响因子：
5.7
作者：
Festoff, BM;D'Andrea, MR;Andrade-Gordon, P
通讯作者：
Andrade-Gordon, P
影响因子：
6.2
作者：
Burda, Joshua E.;Radulovic, Maja;Yoon, Hyesook;Scarisbrick, Isobel A.
通讯作者：
Scarisbrick, Isobel A.
影响因子：
5.3
作者：
Junge, CE;Lee, CJ;Traynelis, SF
通讯作者：
Traynelis, SF
影响因子：
4.2
作者：
Itsekson-Hayosh, Zeev;Shavit-Stein, Efrat;Pick, Chaim G.
通讯作者：
Pick, Chaim G.
影响因子：
4.6
作者：
Allen M;Ghosh S;Ahern GP;Villapol S;Maguire-Zeiss KA;Conant K
通讯作者：
Conant K