Autor: |
Rikke H. Kofoed, Jin Zheng, Nelson Ferreira, Søren Lykke-Andersen, Mauro Salvi, Cristine Betzer, Lasse Reimer, Torben Heick Jensen, Karina Fog, Poul H. Jensen |
Jazyk: |
angličtina |
Rok vydání: |
2017 |
Předmět: |
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Zdroj: |
Neurobiology of Disease, Vol 106, Iss , Pp 49-62 (2017) |
Druh dokumentu: |
article |
ISSN: |
1095-953X |
DOI: |
10.1016/j.nbd.2017.06.014 |
Popis: |
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 10 days' 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. |
Databáze: |
Directory of Open Access Journals |
Externí odkaz: |
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