Neuronal overexpression of IP3 receptor 2 is detrimental in mutant SOD1 mice
Neuronal overexpression of IP3 receptor 2 is detrimental in mutant SOD1 mice
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IP3 受体 2 的神经元过度表达对突变 SOD1 小鼠有害
DOI：
10.1016/j.bbrc.2012.10.094
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Staats KA
中科院分区：
文献类型：
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作者：
D. Kulic;W. Takano and Y. Nakamura;酒井邦嘉;Staats KA
肌萎缩侧索硬化症（Amyotrophic Lateral Sclerosis，ALS）是一种严重的神经退行性疾病，可导致患者进行性瘫痪，并在确诊后平均3- 5年内死亡。疾病病理学是多因素的，包括通过胞质Ca 2+过载诱导细胞死亡的兴奋性毒性过程。在这项研究中，我们增加了内质网（ER）的钙释放通道，肌醇1，4，5-三磷酸受体2（IP 3R 2）的神经元表达，以评估是否增加胞质钙2+起源于ER是有害的神经元。使用Thy1.2-IP 3R 2构建体在N2 a细胞中过表达IP 3R 2增加缓激肽诱发的胞浆Ca 2+浓度。此外，由该构建体产生的小鼠在脊髓和脑中具有增加的IP 3R 2表达。IP 3R 2的这种过表达不影响症状发作，但显著缩短了ALS小鼠的疾病持续时间和寿命。这些数据表明，ER Ca 2+释放的IP 3受体可能是有害的ALS和运动神经元容易受损的Ca 2+代谢。
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease causing progressive paralysis of the patient followed by death on average 3–5years after diagnosis. Disease pathology is multi-factorial including the process of excitotoxicity that induces cell death by cytosolic Ca2+overload. In this study, we increased the neuronal expression of an endoplasmic reticulum (ER) Ca2+release channel, inositol 1,4,5-trisphosphate receptor 2 (IP3R2), to assess whether increased cytosolic Ca2+originating from the ER is detrimental for neurons. Overexpression of IP3R2 in N2a cells using a Thy1.2–IP3R2 construct increases cytosolic Ca2+concentrations evoked by bradykinin. In addition, mice generated from this construct have increased expression of IP3R2 in the spinal cord and brain. This overexpression of IP3R2 does not affect symptom onset, but decreases disease duration and shortens the lifespan of the ALS mice significantly. These data suggest that ER Ca2+released by IP3receptors may be detrimental in ALS and that motor neurons are vulnerable to impaired Ca2+metabolism.