Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/140921
Title: | Nuclear localization and phosphorylation modulate pathological effects of α-synuclein |
Author: | Pinho, Raquel Paiva, Isabel Jercic, Kristina Gotovac Fonseca-Ornelas, Luis Gerhardt, Ellen Fahlbusch, Cristiane Garcia Esparcia, Paula Kerimoglu, Cemil Pavlou, Maria A. Villar Piqué, Anna Szego, Éva Lopes da Fonseca, Tomás Odoardi, Francesca Soeroes, Szabolcs Rego, Ana Cristina Fischle, Wolfgang Schwamborn, Jens C. Meyer, Thomas Kügler, Sebastian Ferrer, Isidro (Ferrer Abizanda) Attems, Johannes Fischer, Andre Becker, Stefan Zweckstetter, Markus Borovecki, Fran Outeiro, Tiago F. |
Keywords: | Alfa-sinucleïna Metabolisme Fisiologia Alpha-synuclein Metabolism Physiology |
Issue Date: | 1-Jan-2019 |
Publisher: | Oxford University Press |
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 to 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. |
Note: | Versió postprint del document publicat a: https://doi.org/10.1093/hmg/ddy326 |
It is part of: | Human Molecular Genetics, 2019, vol. 28, num. 1, p. 31-50 |
URI: | http://hdl.handle.net/2445/140921 |
Related resource: | https://doi.org/10.1093/hmg/ddy326 |
ISSN: | 0964-6906 |
Appears in Collections: | Articles publicats en revistes (Patologia i Terapèutica Experimental) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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689448.pdf | 1.39 MB | Adobe PDF | View/Open |
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