Chronic suppression of STIM1-mediated calcium signaling in Purkinje cells rescues the cerebellar pathology in spinocerebellar ataxia type 2
Chronic suppression of STIM1-mediated calcium signaling in Purkinje cells rescues the cerebellar pathology in spinocerebellar ataxia type 2
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DOI：
10.1016/j.bbamcr.2023.119466
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发表时间：
2023-03-21
影响因子：
5.1
通讯作者：
Bezprozvanny, Ilya B.
中科院分区：
文献类型：
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作者：
Egorova, Polina A.;Marinina, Ksenia S.;Bezprozvanny, Ilya B.
据报道，许多神经退行性疾病中神经元钙信号传导扭曲，包括不同类型的脊髓小脑共济失调 (SCA)。小脑浦肯野细胞 (PC) 主要在 SCA 中受到影响，并且在 SCA PC 中观察到钙稳态的紊乱。我们之前的结果表明，与野生型 (WT) PC 培养物相比，3,5二羟基苯基甘氨酸 (DHPG) 在 SCA2-58Q PC 培养物中诱导更强的钙反应。在这里，我们观察到，与同龄的 WT PC 相比，来自急性小脑切片的 SCA2-58Q PC 中谷氨酸诱导的 PC 细胞体钙释放显着更高。最近的研究表明，基质相互作用分子 1 (STIM1) 在小鼠小脑 PC 神经元钙信号传导的调节中发挥着重要作用。 STIM1 的主要功能是通过 TRPC/Orai 通道的形成调节钙库操作的钙进入，以在 ER 空时补充钙库。在这里，我们证明，在小脑 PC 中特异性靶向 STIM1 的小干扰 RNA (siRNA) 的慢性病毒介导表达可减轻 SCA2-58Q PC 中钙信号紊乱，挽救这些小脑神经元的脊柱损失，并改善 SCA2-58Q 小鼠的运动衰退。因此，我们的初步结果支持神经元钙信号传导改变在 SCA2 病理学中的重要作用，并表明 STIM1 介导的信号传导途径作为 SCA2 患者治疗的潜在治疗靶点。
Distorted neuronal calcium signaling has been reported in many neurodegenerative disorders, including different types of spinocerebellar ataxias (SCAs). Cerebellar Purkinje cells (PCs) are primarily affected in SCAs and the disturbances in the calcium homeostasis were observed in SCA PCs. Our previous results have revealed that 3,5dihydroxyphenylglycine (DHPG) induced greater calcium responses in SCA2-58Q PC cultures than in wild type (WT) PC cultures. Here we observed that glutamate-induced calcium release in PCs cells bodies is significantly higher in SCA2-58Q PCs from acute cerebellar slices compared to WT PCs of the same age. Recent studies have demonstrated that the stromal interaction molecule 1 (STIM1) plays an important role in the regulation of the neuronal calcium signaling in cerebellar PCs in mice. The main function of STIM1 is to regulate store-operated calcium entry through the TRPC/Orai channels formation to refill the calcium stores in the ER when it is empty. Here we demonstrated that the chronic viral-mediated expression of the small interfering RNA (siRNA) targeting STIM1 specifically in cerebellar PCs alleviates the deranged calcium signaling in SCA2-58Q PCs, rescues the spine loss in these cerebellar neurons, and also improves the motor decline in SCA2-58Q mice. Thus, our preliminary results support the important role of the altered neuronal calcium signaling in SCA2 pathology and also suggest the STIM1-mediated signaling pathway as a potential therapeutic target for treatment of SCA2 patients.