TRPA1 deficiency is protective in cuprizone‐induced demyelination—A new target against oligodendrocyte apoptosis
TRPA1 deficiency is protective in cuprizone‐induced demyelination—A new target against oligodendrocyte apoptosis
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DOI：
10.1002/glia.23051
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发表时间：
2016-08
期刊：
影响因子：
6.2
通讯作者：
É. Sághy;É. Sipos;P. Ács;K. Bölcskei;K. Pohóczky;Á. Kemény;Z. Sándor;É. Szőke;G. Sétáló;S. Komoly;E. Pintér
中科院分区：
文献类型：
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作者：
É. Sághy;É. Sipos;P. Ács;K. Bölcskei;K. Pohóczky;Á. Kemény;Z. Sándor;É. Szőke;G. Sétáló;S. Komoly;E. Pintér
多发性硬化症是一种慢性炎症性、脱髓鞘性中枢神经系统退行性疾病。目前的治疗靶向病理性免疫反应以抵消炎症过程。然而，这些药物不能抑制临床残疾的长期进展。因此，需要新的治疗方法和鉴定新的靶分子来预防脱髓鞘或促进修复机制。瞬时受体电位锚蛋白1（TRPA 1）是一种具有相对高的Ca 2+渗透性的非选择性阳离子通道。其在中枢神经系统疾病中的病理生理作用尚未阐明。在本研究中，我们的目的是评估TRPA 1在小鼠脑中的分布，并揭示其在cuprizone诱导的脱髓鞘中的调节作用。这种毒素诱导的模型，其特征在于少突胶质细胞凋亡和随后的原发性脱髓鞘，使我们能够研究多发性硬化症的非免疫方面。我们发现TRPA 1在小鼠中枢神经系统的星形胶质细胞上表达。有趣的是，TRPA 1缺乏通过减少成熟少突胶质细胞的凋亡显著减弱了铜腙诱导的脱髓鞘。我们的数据表明，TRPA 1调节丝裂原活化蛋白激酶途径，以及转录因子c-Jun和促凋亡Bcl-2家族成员（巴克）的表达，导致少突胶质细胞凋亡增强。总之，我们提出TRPA 1受体增强细胞内Ca 2+浓度调节星形胶质细胞功能，并影响少突胶质细胞中的促或抗凋亡途径。TRPA 1受体的抑制可能会成功地减少多发性硬化症的退行性病变，并可能是一个有前途的治疗目标，以限制中枢神经系统损伤的脱髓鞘疾病。GLIA 2016;64：2166-2180
Multiple sclerosis is a chronic inflammatory, demyelinating degenerative disease of the central nervous system. Current treatments target pathological immune responses to counteract the inflammatory processes. However, these drugs do not restrain the long‐term progression of clinical disability. For this reason, new therapeutic approaches and identification of novel target molecules are needed to prevent demyelination or promote repair mechanisms. Transient Receptor Potential Ankyrin 1 (TRPA1) is a nonselective cation channel with relatively high Ca2+ permeability. Its pathophysiological role in central nervous system disorders has not been elucidated yet. In the present study, we aimed to assess the distribution of TRPA1 in the mouse brain and reveal its regulatory role in the cuprizone‐induced demyelination. This toxin‐induced model, characterized by oligodendrocyte apoptosis and subsequent primary demyelination, allows us to investigate the nonimmune aspects of multiple sclerosis. We found that TRPA1 is expressed on astrocytes in the mouse central nervous system. Interestingly, TRPA1 deficiency significantly attenuated cuprizone‐induced demyelination by reducing the apoptosis of mature oligodendrocytes. Our data suggest that TRPA1 regulates mitogen‐activated protein kinase pathways, as well as transcription factor c‐Jun and a proapoptotic Bcl‐2 family member (Bak) expression resulting in enhanced oligodendrocyte apoptosis. In conclusion, we propose that TRPA1 receptors enhancing the intracellular Ca2+ concentration modulate astrocyte functions, and influence the pro or anti‐apoptotic pathways in oligodendrocytes. Inhibition of TRPA1 receptors might successfully diminish the degenerative pathology in multiple sclerosis and could be a promising therapeutic target to limit central nervous system damage in demyelinating diseases. GLIA 2016;64:2166–2180