Selenoprotein T Promotes Proliferation and G1-to-S Transition in SK-N-SH Cells: Implications in Parkinson's Disease

• Published in: The Journal of nutrition Vol. 149; no. 12; pp. 2110 - 2119
• Main Authors: Shao, Zi-Qiang, Zhang, Xiong, Fan, Hui-Hui, Wang, Xiao-Shuang, Wu, Hong-Mei, Zhang, Li, Cheng, Wen-Hsing, Zhu, Jian-Hong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2019; Oxford University Press; American Institute of Nutrition
• Subjects: 6-Hydroxydopamine; acetylcysteine; Aged; Animals; Annexin V; Antioxidants; Blood; brain; Calcium; Calcium - metabolism; Calcium channel blockers; Calcium channels; Caspase-3; Cell cycle; cell cycle checkpoints; Cell Line; Cell proliferation; Cell Proliferation - physiology; Cyclin-dependent kinase; Cyclin-dependent kinase 4; Cyclin-dependent kinase inhibitor p27; Cysteine; Dopamine receptors; Female; Flow cytometry; Forkhead protein; G1 Phase - physiology; Humans; Hydroxylase; Immunoblotting; Iodides; Kinases; Leukocytes (mononuclear); Male; males; Mice; Mice, Inbred C57BL; Middle Aged; Movement disorders; mRNA; Neurodegenerative diseases; Neurons; Nimodipine; nutrition; oxidative stress; Parkinson disease; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; S Phase - physiology; Selenium; selenoprotein; selenoproteins; Selenoproteins - physiology; Tyrosine; Up-Regulation; Vitamins; Parkinson's disease; CDKN1B; 6-OHDA; CDK; FOXO3; MPP; SELENOH; selenium; CCND1; siSELT; CDKN2D; calcium; CDKN2C; GPX1; GPX4; TXNRD1; siRNA; PBMC; selenoprotein; NAC; PD; CCNE1; EdU; ROS; SELENOP; SELENOT; oxidative stress
• ISSN: 0022-3166; 1541-6100; 1541-6100
• 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-phenylpyrefidinium 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′-deoxyurefidine 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.