The thrombin receptor links brain derived neurotrophic factor to neuron cholesterol production, resiliency and repair after spinal cord injury.
The thrombin receptor links brain derived neurotrophic factor to neuron cholesterol production, resiliency and repair after spinal cord injury.
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DOI：
10.1016/j.nbd.2021.105294
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发表时间：
2021-05
影响因子：
6.1
通讯作者：
Scarisbrick IA
中科院分区：
文献类型：
--
作者：
Triplet EM;Kim HN;Yoon H;Radulovic M;Kleppe L;Simon WL;Choi CI;Walsh PJ;Dutton JR;Scarisbrick IA
尽管各方共同努力确定中枢神经系统再生策略，但对所需分子机制如何调控的不完全理解限制了进展。在这里，我们使用侧压和FEJOTA夹挫伤-压缩性脊髓损伤（SCI）模型来确定凝血酶受体（蛋白酶激活受体1 (PAR1)）作为该机器的一个组成部分，通过生长因子和胆固醇依赖机制调节神经突生长。PAR1基因敲除雌性小鼠脊髓损伤后，功能恢复和神经修复的迹象，包括胆固醇生物合成机制和轴突和突触完整性标志物的表达均增加，而PTEN降低。值得注意的是，PAR1在完整脊髓和受损脊髓的神经元和星形胶质区室中对HMGCS1（一种编码胆固醇生成限速酶的基因）的调节存在差异。体外用vorapaxar对皮质神经元PAR1的药理学抑制也降低了PTEN并以胆固醇依赖的方式促进了神经突的生长，包括由次优脑源性神经营养因子（BDNF）驱动的生长。PAR1的药理学抑制也增强了bdnf驱动的HMGCS1和小鼠皮质神经元以及人SH-SY5Y和ipsc衍生神经元的胆固醇生成。PAR1、胆固醇和BDNF之间的联系被进一步强调，证明PAR1过度激活的有害影响可以通过补充BDNF、胆固醇或阻断腺苷酸环化酶抑制剂g - αi来克服。这些发现证明了par1相关的神经营养偶联机制调节神经元胆固醇代谢是调节中枢神经系统修复机制的重要组成部分，并指出了增强损伤后神经弹性的新策略。
Despite concerted efforts to identify CNS regeneration strategies, an incomplete understanding of how the needed molecular machinery is regulated limits progress. Here we use models of lateral compression and FEJOTA clip contusion-compression spinal cord injury (SCI) to identify the thrombin receptor (Protease Activated Receptor 1 (PAR1)) as an integral facet of this machine with roles in regulating neurite growth through a growth factor- and cholesterol-dependent mechanism. Functional recovery and signs of neural repair, including expression of cholesterol biosynthesis machinery and markers of axonal and synaptic integrity, were all increased after SCI in PAR1 knockout female mice, while PTEN was decreased. Notably, PAR1 differentially regulated HMGCS1, a gene encoding a rate-limiting enzyme in cholesterol production, across the neuronal and astroglial compartments of the intact versus injured spinal cord. Pharmacologic inhibition of cortical neuron PAR1 using vorapaxar in vitro also decreased PTEN and promoted neurite outgrowth in a cholesterol dependent manner, including that driven by suboptimal brain derived neurotrophic factor (BDNF). Pharmacologic inhibition of PAR1 also augmented BDNF-driven HMGCS1 and cholesterol production by murine cortical neurons and by human SH-SY5Y and iPSC-derived neurons. The link between PAR1, cholesterol and BDNF was further highlighted by demonstrating that the deleterious effects of PAR1 over-activation are overcome by supplementing cultures with BDNF, cholesterol or by blocking an inhibitor of adenylate cyclase, Gαi. These findings document PAR1-linked neurotrophic coupling mechanisms that regulate neuronal cholesterol metabolism as an important component of the machinery regulating CNS repair and point to new strategies to enhance neural resiliency after injury.
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影响因子：
3.7
作者：
Geng Z;Walsh PJ;Truong V;Hill C;Ebeling M;Kapphahn RJ;Montezuma SR;Yuan C;Roehrich H;Ferrington DA;Dutton JR
通讯作者：
Dutton JR
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
--
作者：
Göritz, C;Mauch, DH;Pfrieger, FW
通讯作者：
Pfrieger, FW
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：
Baydyuk M;Xu B
通讯作者：
Xu B