Department of Geriatrics and Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
J Nutr. 2019 Dec 1;149(12):2110-2119. doi: 10.1093/jn/nxz199.
Selenium is prioritized to the brain mainly for selenoprotein expression. Selenoprotein T (SELENOT) protects dopaminergic, postmitotic neurons in a mouse model of Parkinson's disease (PD).
We hypothesized a proliferative role of SELENOT in neural cells.
To assess SELENOT status in PD, sedated male C57BL/6 mice at 10-12 wk of age were injected with 6-hydroxydopamine in neurons, and human peripheral blood mononuclear cells were isolated from 9 healthy subjects (56% men, 68-y-old) and 11 subjects with PD (64% men, 63-y-old). Dopaminergic neural progenitor-like SK-N-SH cells with transient SELENOT overexpression or knockdown were maintained in the presence or absence of the antioxidant N-acetyl-l-cysteine and the calcium channel blocker nimodipine. Cell cycle, proliferation, and signaling parameters were determined by immunoblotting, qPCR, and flow cytometry.
SELENOT mRNA abundance was increased (P < 0.05) in SK-N-SH cells treated with 1-methyl-4-phenylpyridinium iodide (3.5-fold) and peripheral blood mononuclear cells from PD patients (1.6-fold). Likewise, SELENOT was expressed in tyrosine hydroxylase-positive dopaminergic neurons of 6-hydroxydopamine-injected mice. Knockdown of SELENOT in SK-N-SH cells suppressed (54%; P < 0.05) 5-ethynyl-2'-deoxyuridine incorporation but induced (17-47%; P < 0.05) annexin V-positive cells, CASPASE-3 cleavage, and G1/S cell cycle arrest. SELENOT knockdown and overexpression increased (88-120%; P < 0.05) and reduced (37-42%; P < 0.05) both forkhead box O3 and p27, but reduced (51%; P < 0.05) and increased (1.2-fold; P < 0.05) cyclin-dependent kinase 4 protein abundance, respectively. These protein changes were diminished by nimodipine or N-acetyl-l-cysteine treatment (24 h) at steady-state levels. While the N-acetyl-l-cysteine treatment did not influence the reduction in the amount of calcium (13%; P < 0.05) by SELENOT knockdown, the nimodipine treatment reversed the decreased amount of reactive oxygen species (33%; P < 0.05) by SELENOT overexpression.
These cellular and mouse data link SELENOT to neural proliferation, expanding our understanding of selenium protection in PD.
硒主要通过表达硒蛋白优先分配到大脑。硒蛋白 T（SELENOT）在帕金森病（PD）的小鼠模型中保护多巴胺能、有丝分裂后神经元。
我们假设 SELENOT 在神经细胞中具有增殖作用。
为了评估 PD 中的 SELENOT 状态，10-12 周龄的镇静雄性 C57BL/6 小鼠被注射到神经元中的 6-羟多巴胺中，并且从 9 名健康受试者（56%男性，68 岁）和 11 名 PD 受试者（64%男性，63 岁）中分离出人外周血单核细胞。具有瞬时 SELENOT 过表达或敲低的多巴胺能神经祖细胞样 SK-N-SH 细胞在抗氧化剂 N-乙酰-L-半胱氨酸和钙通道阻滞剂尼莫地平的存在或不存在下维持。通过免疫印迹、qPCR 和流式细胞术测定细胞周期、增殖和信号转导参数。
用 1-甲基-4-苯基吡啶鎓碘化物（3.5 倍）处理的 SK-N-SH 细胞和 PD 患者外周血单核细胞中的 SELENOT mRNA 丰度增加（P<0.05）。同样，SELENOT 在 6-羟多巴胺注射小鼠的酪氨酸羟化酶阳性多巴胺能神经元中表达。SK-N-SH 细胞中的 SELENOT 敲低抑制（54%；P<0.05）5-乙炔基-2'-脱氧尿苷掺入，但诱导（17-47%；P<0.05）膜联蛋白 V 阳性细胞、CASPASE-3 切割和 G1/S 细胞周期阻滞。SELENOT 敲低和过表达分别增加（88-120%；P<0.05）和减少（37-42%；P<0.05）叉头框 O3 和 p27，但减少（51%；P<0.05）和增加（1.2 倍；P<0.05）细胞周期蛋白依赖性激酶 4 蛋白丰度。这些蛋白质变化在稳定状态下用尼莫地平或 N-乙酰-L-半胱氨酸处理（24 小时）时减弱。虽然 N-乙酰-L-半胱氨酸处理不影响 SELENOT 敲低导致的钙减少（13%；P<0.05），但尼莫地平处理逆转了 SELENOT 过表达导致的活性氧减少（33%；P<0.05）。
这些细胞和小鼠数据将 SELENOT 与神经增殖联系起来，扩展了我们对硒在 PD 中保护作用的理解。
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