Hyperphosphorylation of Tau Due to the Interference of Protein Phosphatase Methylesterase-1 Overexpression by MiR-125b-5p in Melatonin Receptor Knockout Mice

Melatonin has been indicated to ameliorate tau hyperphosphorylation in the pathogenesis of tau diseases, but the role of melatonin-receptor signal transduction has not been clearly discovered. In this study, we found intensive tau hyperphosphorylation in melatonin receptor knockout mice. Bielschowsk...

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Autores principales:	Han Zhao, Lingyan Feng, Wei Zhong, Hongyan Zhen, Qingjia Chi, Xiang Wang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	melatonin PME-1 mmu-miR-125b-5p neurofibrillary tangles protein phosphatase 2A tau Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/ffe0ce70e19c4221b32c018f7a49f845
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spelling	oai:doaj.org-article:ffe0ce70e19c4221b32c018f7a49f8452021-11-11T17:16:39ZHyperphosphorylation of Tau Due to the Interference of Protein Phosphatase Methylesterase-1 Overexpression by MiR-125b-5p in Melatonin Receptor Knockout Mice10.3390/ijms2221118501422-00671661-6596https://doaj.org/article/ffe0ce70e19c4221b32c018f7a49f8452021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11850https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Melatonin has been indicated to ameliorate tau hyperphosphorylation in the pathogenesis of tau diseases, but the role of melatonin-receptor signal transduction has not been clearly discovered. In this study, we found intensive tau hyperphosphorylation in melatonin receptor knockout mice. Bielschowsky silver staining showed ghostlike neurofibrillary tangles in melatonin receptor-2 knockout (MT2KO) as well as melatonin receptors-1 and -2 knockout (DKO) mice, and an argyrophilic substance was deposited in melatonin receptor-1 knockout (MT1KO) mice. Furthermore, we found significantly decreased activity of protein phosphatase 2A (PP2A) by Western blot and enzyme-linked immunosorbent assay (ELISA), which was partly due to the overexpression of protein phosphatase methylesterase-1 (PME-1), but not glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (CDK5) or protein kinase B (Akt). Finally, we observed a significant increase in cyclic adenosine monophosphate (cAMP) and a decrease in miR-125b-5p levels in MT1KO, MT2KO and DKO mice. Using a luciferase reporter assay, we discovered that miR-125b-5p largely decreased the expression of firefly luciferase by interfering with the 3′UTR of PME-1. Furthermore, miR-125b-5p mimics significantly decreased the expression of PME-1, while miR-125b-5p inhibitor induced tau hyperphosphorylation. These results show that melatonin-receptor signal transduction plays an important role in tau hyperphosphorylation and tangle formation.Han ZhaoLingyan FengWei ZhongHongyan ZhenQingjia ChiXiang WangMDPI AGarticlemelatoninPME-1mmu-miR-125b-5pneurofibrillary tanglesprotein phosphatase 2AtauBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11850, p 11850 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	melatonin PME-1 mmu-miR-125b-5p neurofibrillary tangles protein phosphatase 2A tau Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	melatonin PME-1 mmu-miR-125b-5p neurofibrillary tangles protein phosphatase 2A tau Biology (General) QH301-705.5 Chemistry QD1-999 Han Zhao Lingyan Feng Wei Zhong Hongyan Zhen Qingjia Chi Xiang Wang Hyperphosphorylation of Tau Due to the Interference of Protein Phosphatase Methylesterase-1 Overexpression by MiR-125b-5p in Melatonin Receptor Knockout Mice
description	Melatonin has been indicated to ameliorate tau hyperphosphorylation in the pathogenesis of tau diseases, but the role of melatonin-receptor signal transduction has not been clearly discovered. In this study, we found intensive tau hyperphosphorylation in melatonin receptor knockout mice. Bielschowsky silver staining showed ghostlike neurofibrillary tangles in melatonin receptor-2 knockout (MT2KO) as well as melatonin receptors-1 and -2 knockout (DKO) mice, and an argyrophilic substance was deposited in melatonin receptor-1 knockout (MT1KO) mice. Furthermore, we found significantly decreased activity of protein phosphatase 2A (PP2A) by Western blot and enzyme-linked immunosorbent assay (ELISA), which was partly due to the overexpression of protein phosphatase methylesterase-1 (PME-1), but not glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (CDK5) or protein kinase B (Akt). Finally, we observed a significant increase in cyclic adenosine monophosphate (cAMP) and a decrease in miR-125b-5p levels in MT1KO, MT2KO and DKO mice. Using a luciferase reporter assay, we discovered that miR-125b-5p largely decreased the expression of firefly luciferase by interfering with the 3′UTR of PME-1. Furthermore, miR-125b-5p mimics significantly decreased the expression of PME-1, while miR-125b-5p inhibitor induced tau hyperphosphorylation. These results show that melatonin-receptor signal transduction plays an important role in tau hyperphosphorylation and tangle formation.
format	article
author	Han Zhao Lingyan Feng Wei Zhong Hongyan Zhen Qingjia Chi Xiang Wang
author_facet	Han Zhao Lingyan Feng Wei Zhong Hongyan Zhen Qingjia Chi Xiang Wang
author_sort	Han Zhao
title	Hyperphosphorylation of Tau Due to the Interference of Protein Phosphatase Methylesterase-1 Overexpression by MiR-125b-5p in Melatonin Receptor Knockout Mice
title_short	Hyperphosphorylation of Tau Due to the Interference of Protein Phosphatase Methylesterase-1 Overexpression by MiR-125b-5p in Melatonin Receptor Knockout Mice
title_full	Hyperphosphorylation of Tau Due to the Interference of Protein Phosphatase Methylesterase-1 Overexpression by MiR-125b-5p in Melatonin Receptor Knockout Mice
title_fullStr	Hyperphosphorylation of Tau Due to the Interference of Protein Phosphatase Methylesterase-1 Overexpression by MiR-125b-5p in Melatonin Receptor Knockout Mice
title_full_unstemmed	Hyperphosphorylation of Tau Due to the Interference of Protein Phosphatase Methylesterase-1 Overexpression by MiR-125b-5p in Melatonin Receptor Knockout Mice
title_sort	hyperphosphorylation of tau due to the interference of protein phosphatase methylesterase-1 overexpression by mir-125b-5p in melatonin receptor knockout mice
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ffe0ce70e19c4221b32c018f7a49f845
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Hyperphosphorylation of Tau Due to the Interference of Protein Phosphatase Methylesterase-1 Overexpression by MiR-125b-5p in Melatonin Receptor Knockout Mice

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