Toggle Main Menu Toggle Search

Open Access padlockePrints

Nuclear localization and phosphorylation modulate pathological effects of alpha-synuclein

Lookup NU author(s): Dr Thomas Meyer, Professor Johannes Attems, Professor Tiago Outeiro

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Abstract

Alpha-synuclein (aSyn) is a central player in Parkinson's disease (PD) but the precise molecular mechanisms underlying its pathogenicity remain unclear. It has recently been suggested that nuclear aSyn may modulate gene expression, possibly via interactions with DNA. However, the biological behavior of aSyn in the nucleus and the factors affecting its transcriptional role are not known. Here, we investigated the mechanisms underlying aSyn-mediated transcription deregulation by assessing its effects in the nucleus and the impact of phosphorylation in these dynamics. We found that aSyn induced severe transcriptional deregulation, including the downregulation of important cell cycle-related genes. Importantly, transcriptional deregulation was concomitant with reduced binding of aSyn to DNA. By forcing the nuclear presence of aSyn in the nucleus (aSyn-NLS), we found the accumulation of high molecular weight aSyn species altered gene expression and reduced toxicity when compared with the wild-type or exclusively cytosolic protein. Interestingly, nuclear localization of aSyn, and the effect on gene expression and cytotoxicity, was also modulated by phosphorylation on serine 129. Thus, we hypothesize that the role of aSyn on gene expression and, ultimately, toxicity, may be modulated by the phosphorylation status and nuclear presence of different aSyn species. Our findings shed new light onto the subcellular dynamics of aSyn and unveil an intricate interplay between subcellular location, phosphorylation and toxicity, opening novel avenues for the design of future strategies for therapeutic intervention in PD and other synucleinopathies.


Publication metadata

Author(s): Pinho R, Paiva I, Jercic KG, Fonseca-Ornelas L, Gerhardt E, Fahlbusch C, Garcia-Esparcia P, Kerimoglu C, Pavlou MAS, Villar-Pique A, Szego E, Lopes da Fonseca T, Odoardi F, Soeroes S, Rego AC, Fischle W, Schwamborn JC, Meyer T, Kugler S, Ferrer I, Attems J, Fischer A, Becker S, Zweckstetter M, Borovecki F, Outeiro TF

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2019

Volume: 28

Issue: 1

Pages: 31-50

Print publication date: 01/01/2019

Online publication date: 13/09/2018

Acceptance date: 10/09/2018

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press

URL: https://doi.org/10.1093/hmg/ddy326

DOI: 10.1093/hmg/ddy326

PubMed id: 30219847


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share