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  Nuclear localization and phosphorylation modulate pathological effects of alpha-synuclein.

Pinho, R., Paiva, I., Jerčić, K. G., Fonseca-Ornelas, L., Gerhardt, E., Fahlbusch, C., et al. (2019). Nuclear localization and phosphorylation modulate pathological effects of alpha-synuclein. Human Molecular Genetics, 28(1), 31-50. doi:10.1093/hmg/ddy326.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-18BB-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0002-B7BA-E
Genre: Journal Article

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 Creators:
Pinho, R., Author
Paiva, I., Author
Jerčić, K. G., Author
Fonseca-Ornelas, L., Author
Gerhardt, E., Author
Fahlbusch, C., Author
Garcia-Esparcia, P., Author
Kerimoglu, C., Author
Pavlou, M. A., Author
Villar-Piqué, A., Author
Szegő, E., Author
Fonseca, T. L., Author
Odoardi, F., Author
Soeroes, S., Author
Rego, A. C., Author
Fischle, W.1, Author              
Schwamborn, J. C., Author
Meyer, T., Author
Kügler, S., Author
Ferrer, I., Author
Attems, J., AuthorFischer, A., AuthorBecker, S.2, Author              Zweckstetter, M.3, Author              Borovecki, F., AuthorOuteiro, T. F., Author more..
Affiliations:
1Research Group of Chromatin Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578604              
2Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
3Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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 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.

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Language(s): eng - English
 Dates: 2018-09-132019-01-01
 Publication Status: Published in print
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1093/hmg/ddy326
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Title: Human Molecular Genetics
Source Genre: Journal
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Pages: - Volume / Issue: 28 (1) Sequence Number: - Start / End Page: 31 - 50 Identifier: -