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Hum Mol Genet. 2019 Jan 1;28(1):31-50. doi: 10.1093/hmg/ddy326.

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

Author information

1
Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany.
2
Faculty of Medicine, University of Porto, Porto, Portugal.
3
Department for Functional Genomics, Center for Translational and Clinical Research, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia.
4
Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
5
Institute of Neuropathology, Bellvitge University Hospital, University of Barcelona, Bellvitge Biomedical Research Institute, Hospitalet de Llobregat; Biomedical Research Center of Neurodegenerative Diseases, Barcelona, Spain.
6
Department for Psychiatry and Psychotherapy, University Medical Center, Göttingen, Germany.
7
Institute of Neuroimmunology and Institute for Multiple Sclerosis Research, University Medical Centre Göttingen, Göttingen, Germany.
8
Max Planck Institute for Biophysical Chemistry, Laboratory of Chromatin Biochemistry, Göttingen, Germany.
9
Oxford Nanopore Technologies LTD, Oxford, United Kingdom.
10
Center for Neuroscience and Cell Biology and Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
11
King Abdullah University of Science and Technology, Environmental Epigenetics Program, Thuwal, Saudi Arabia.
12
Development and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.
13
Klinik für Psychosomatische Medizin und Psychotherapie, Universitätsmedizin Göttingen, Göttingen, Germany.
14
Department of Neurology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany.
15
Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom.
16
Department of Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Göttingen Germany.
17
Structural Biology in Dementia, German Center for Neurodegenerative Diseases, Göttingen, Germany.
18
Department of Neurology, University Hospital Center Zagreb, Zagreb, Croatia.
19
Chronic Disease Research Center, NOVA Medical School, Lisboa, Portugal.
20
Max Planck Institute for Experimental Medicine, Göttingen, Germany.

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.

PMID:
30219847
DOI:
10.1093/hmg/ddy326
[Indexed for MEDLINE]

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