Neurotoxin-Induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling
Neurotoxin-Induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling
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DOI：
10.1172/jci61332
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发表时间：
2012-04-01
影响因子：
15.9
通讯作者：
Singh, Brij B.
中科院分区：
文献类型：
--
作者：
Selvaraj, Senthil;Sun, Yuyang;Singh, Brij B.
帕金森病（PD）患者由于黑质中多巴胺能（DA）神经元的选择性丧失而经历运动功能的进行性下降。DA神经元丢失的潜在机制尚不清楚。在这里，我们表明，一种神经毒素，导致一种疾病，模仿PD后，给药小鼠，因为它诱导黑质DA神经元的选择性损失，改变Ca 2+稳态，并诱导ER应激。在人神经母细胞瘤细胞系中，我们发现内源性钙库操纵的钙内流（SOCE），这是维持ER钙水平的关键，是依赖于瞬时受体电位通道1（TRPC 1）的活动。神经毒素处理降低TRPC 1表达，TRPC 1与SOCE调节剂基质相互作用分子1（STIM 1）的相互作用，以及Ca 2+进入细胞。功能性TRPC 1的过表达可防止神经毒素诱导的SOCE丧失、相关的ER Ca 2+水平降低以及由此产生的未折叠蛋白反应（UPR）。相反，TRPC 1或STIM 1的沉默增加了UPR。此外，通过TRPC 1的Ca 2+进入激活AKT通路，其在神经保护中具有已知的作用。与这些体外数据一致，Trpc 1（-/-）小鼠的UPR增加，DA神经元数量减少。PD患者的脑裂解物也显示UPR增加和TRPC 1水平降低。重要的是，TRPC 1在小鼠中的过表达恢复了AKT/mTOR信号传导，并增加了神经毒素给药后的DA神经元存活。总的来说，这些结果表明TRPC 1参与调节Ca 2+稳态和抑制UPR，从而有助于神经元存活。
Individuals with Parkinson's disease (PD) experience a progressive decline in motor function as a result of selective loss of dopaminergic (DA) neurons in the substantia nigra. The mechanism(s) underlying the loss of DA neurons is not known. Here, we show that a neurotoxin that causes a disease that mimics PD upon administration to mice, because it induces the selective loss of DA neurons in the substantia nigra, alters Ca2+ homeostasis and induces ER stress. In a human neuroblastoma cell line, we found that endogenous store-operated Ca2+ entry (SOCE), which is critical for maintaining ER Ca2+ levels, is dependent on transient receptor potential channel 1 (TRPC1) activity. Neurotoxin treatment decreased TRPC1 expression, TRPC1 interaction with the SOCE modulator stromal interaction molecule 1 (STIM1), and Ca2+ entry into the cells. Overexpression of functional TRPC1 protected against neurotoxin-induced loss of SOCE, the associated decrease in ER Ca2+ levels, and the resultant unfolded protein response (UPR). In contrast, silencing of TRPC1 or STIM1 increased the UPR. Furthermore, Ca2+ entry via TRPC1 activated the AKT pathway, which has a known role in neuroprotection. Consistent with these in vitro data, Trpc1(-/-) mice had an increased UPR and a reduced number of DA neurons. Brain lysates of patients with PD also showed an increased UPR and decreased TRPC1 levels. Importantly, overexpression of TRPC1 in mice restored AKT/mTOR signaling and increased DA neuron survival following neurotoxin administration. Overall, these results suggest that TRPC1 is involved in regulating Ca2+ homeostasis and inhibiting the UPR and thus contributes to neuronal survival.