Poul Henning Jensen

Polo-like kinase 2 modulates α-synuclein protein levels by regulating its mRNA production

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Polo-like kinase 2 modulates α-synuclein protein levels by regulating its mRNA production. / Kofoed, Rikke H; Zheng, Jin; Ferreira, Nelson; Lykke-Andersen, Søren; Salvi, Mauro; Betzer, Cristine; Reimer, Lasse; Jensen, Torben Heick; Fog, Karina; Jensen, Poul Henning.

In: Neurobiology of Disease, Vol. 106, 17.10.2017, p. 49-62.

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@article{150ae30bc6ad49df842133881086a8cc,
title = "Polo-like kinase 2 modulates α-synuclein protein levels by regulating its mRNA production",
abstract = "Variations in the α-synuclein-encoding SNCA gene represent the greatest genetic risk factor for Parkinson's disease (PD), and duplications/triplications of SNCA cause autosomal dominant familial PD. These facts closely link brain levels of α-synuclein with the risk of PD, and make lowering α-synuclein levels a therapeutic strategy for the treatment of PD and related synucleinopathies. In this paper, we corroborate previous findings on the ability of overexpressed Polo-like kinase 2 (PLK-2) to decrease cellular α-synuclein, but demonstrate that the process is independent of PLK-2 phosphorylating S129 in α-synuclein because a similar reduction is achieved with the non-phosphorable S129A mutant α-synuclein. Using a specific PLK-2 inhibitor (compound 37), we demonstrate that endogenous PLK-2 phosphorylates S129 only in some cells, but increases α-synuclein protein levels in all tested cell cultures and brain slices. PLK-2 is found to regulate the transcription of α-synuclein mRNA from both the endogenous mouse SNCA gene and transgenic vectors that only contain the open reading frame. Moreover, we are the first to show that regulation of α-synuclein by PLK-2 is of physiological importance since 10days' inhibition of endogenous PLK-2 in wt C57BL/6 mice increases endogenous α-synuclein protein levels. Our findings collectively demonstrate that PLK-2 regulates α-synuclein levels by a previously undescribed transcription-based mechanism. This mechanism is active in cells and brain tissue, opening up for alternative strategies for modulating α-synuclein levels and thereby for the possibility of modifying disease progression in synucleinopaties.",
keywords = "Journal Article",
author = "Kofoed, {Rikke H} and Jin Zheng and Nelson Ferreira and S{\o}ren Lykke-Andersen and Mauro Salvi and Cristine Betzer and Lasse Reimer and Jensen, {Torben Heick} and Karina Fog and Jensen, {Poul Henning}",
note = "Copyright {\circledC} 2017. Published by Elsevier Inc.",
year = "2017",
month = "10",
day = "17",
doi = "10.1016/j.nbd.2017.06.014",
language = "English",
volume = "106",
pages = "49--62",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press",

}

RIS

TY - JOUR

T1 - Polo-like kinase 2 modulates α-synuclein protein levels by regulating its mRNA production

AU - Kofoed, Rikke H

AU - Zheng, Jin

AU - Ferreira, Nelson

AU - Lykke-Andersen, Søren

AU - Salvi, Mauro

AU - Betzer, Cristine

AU - Reimer, Lasse

AU - Jensen, Torben Heick

AU - Fog, Karina

AU - Jensen, Poul Henning

N1 - Copyright © 2017. Published by Elsevier Inc.

PY - 2017/10/17

Y1 - 2017/10/17

N2 - Variations in the α-synuclein-encoding SNCA gene represent the greatest genetic risk factor for Parkinson's disease (PD), and duplications/triplications of SNCA cause autosomal dominant familial PD. These facts closely link brain levels of α-synuclein with the risk of PD, and make lowering α-synuclein levels a therapeutic strategy for the treatment of PD and related synucleinopathies. In this paper, we corroborate previous findings on the ability of overexpressed Polo-like kinase 2 (PLK-2) to decrease cellular α-synuclein, but demonstrate that the process is independent of PLK-2 phosphorylating S129 in α-synuclein because a similar reduction is achieved with the non-phosphorable S129A mutant α-synuclein. Using a specific PLK-2 inhibitor (compound 37), we demonstrate that endogenous PLK-2 phosphorylates S129 only in some cells, but increases α-synuclein protein levels in all tested cell cultures and brain slices. PLK-2 is found to regulate the transcription of α-synuclein mRNA from both the endogenous mouse SNCA gene and transgenic vectors that only contain the open reading frame. Moreover, we are the first to show that regulation of α-synuclein by PLK-2 is of physiological importance since 10days' inhibition of endogenous PLK-2 in wt C57BL/6 mice increases endogenous α-synuclein protein levels. Our findings collectively demonstrate that PLK-2 regulates α-synuclein levels by a previously undescribed transcription-based mechanism. This mechanism is active in cells and brain tissue, opening up for alternative strategies for modulating α-synuclein levels and thereby for the possibility of modifying disease progression in synucleinopaties.

AB - Variations in the α-synuclein-encoding SNCA gene represent the greatest genetic risk factor for Parkinson's disease (PD), and duplications/triplications of SNCA cause autosomal dominant familial PD. These facts closely link brain levels of α-synuclein with the risk of PD, and make lowering α-synuclein levels a therapeutic strategy for the treatment of PD and related synucleinopathies. In this paper, we corroborate previous findings on the ability of overexpressed Polo-like kinase 2 (PLK-2) to decrease cellular α-synuclein, but demonstrate that the process is independent of PLK-2 phosphorylating S129 in α-synuclein because a similar reduction is achieved with the non-phosphorable S129A mutant α-synuclein. Using a specific PLK-2 inhibitor (compound 37), we demonstrate that endogenous PLK-2 phosphorylates S129 only in some cells, but increases α-synuclein protein levels in all tested cell cultures and brain slices. PLK-2 is found to regulate the transcription of α-synuclein mRNA from both the endogenous mouse SNCA gene and transgenic vectors that only contain the open reading frame. Moreover, we are the first to show that regulation of α-synuclein by PLK-2 is of physiological importance since 10days' inhibition of endogenous PLK-2 in wt C57BL/6 mice increases endogenous α-synuclein protein levels. Our findings collectively demonstrate that PLK-2 regulates α-synuclein levels by a previously undescribed transcription-based mechanism. This mechanism is active in cells and brain tissue, opening up for alternative strategies for modulating α-synuclein levels and thereby for the possibility of modifying disease progression in synucleinopaties.

KW - Journal Article

U2 - 10.1016/j.nbd.2017.06.014

DO - 10.1016/j.nbd.2017.06.014

M3 - Journal article

C2 - 28648742

VL - 106

SP - 49

EP - 62

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

ER -