title: Interplay between sumoylation and phosphorylation for protection against α-synuclein inclusions.
abstract: Parkinson disease is associated with the progressive loss of dopaminergic neurons from the substantia nigra. The pathological hallmark of the disease is the accumulation of intracytoplasmic inclusions known as Lewy bodies that consist mainly of post-translationally modified forms of α-synuclein. Whereas phosphorylation is one of the major modifications of α-synuclein in Lewy bodies, sumoylation has recently been described. The interplay between α-synuclein phosphorylation and sumoylation is poorly understood. Here, we examined the interplay between these modifications as well as their impact on cell growth and inclusion formation in yeast. We found that α-synuclein is sumoylated in vivo at the same sites in yeast as in human cells. Impaired sumoylation resulted in reduced yeast growth combined with an increased number of cells with inclusions, suggesting that this modification plays a protective role. In addition, inhibition of sumoylation prevented autophagy-mediated aggregate clearance. A defect in α-synuclein sumoylation could be suppressed by serine 129 phosphorylation by the human G protein-coupled receptor kinase 5 (GRK5) in yeast. Phosphorylation reduced foci formation, alleviated yeast growth inhibition, and partially rescued autophagic α-synuclein degradation along with the promotion of proteasomal degradation, resulting in aggregate clearance in the absence of a small ubiquitin-like modifier. These findings suggest a complex interplay between sumoylation and phosphorylation in α-synuclein aggregate clearance, which may open new horizons for the development of therapeutic strategies for Parkinson disease.
authors.affiliation: From the Institute of Microbiology and Genetics, Department of Molecular Microbiology and Genetics, Georg-August-Universität Göttingen, D-37077 Göttingen, Germany, the Center for Nanoscale Microscopy and Molecular Physiology of the Brain, D-37073 Göttingen, Germany.
authors.forename: Hedieh
authors.initials: H
authors.lastname: Shahpasandzadeh
authors.affiliation: From the Institute of Microbiology and Genetics, Department of Molecular Microbiology and Genetics, Georg-August-Universität Göttingen, D-37077 Göttingen, Germany, the Center for Nanoscale Microscopy and Molecular Physiology of the Brain, D-37073 Göttingen, Germany.
authors.forename: Blagovesta
authors.initials: B
authors.lastname: Popova
authors.affiliation: From the Institute of Microbiology and Genetics, Department of Molecular Microbiology and Genetics, Georg-August-Universität Göttingen, D-37077 Göttingen, Germany, the Center for Nanoscale Microscopy and Molecular Physiology of the Brain, D-37073 Göttingen, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kleinknecht
authors.affiliation: the Tanz Centre for Research in Neurodegenerative Diseases and Department of Medical Biophysics, University of Toronto, Ontario M5T 2S8, Canada, and.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
authors.affiliation: the Center for Nanoscale Microscopy and Molecular Physiology of the Brain, D-37073 Göttingen, Germany, the Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, D-37073 Göttingen, Germany.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
authors.affiliation: From the Institute of Microbiology and Genetics, Department of Molecular Microbiology and Genetics, Georg-August-Universität Göttingen, D-37077 Göttingen, Germany, the Center for Nanoscale Microscopy and Molecular Physiology of the Brain, D-37073 Göttingen, Germany, gbraus@gwdg.de.
authors.forename: Gerhard H
authors.initials: GH
authors.lastname: Braus
mesh_terms: D001343:Autophagy; D002846:Chromatography, Affinity; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000378:metabolism; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D058207:Sumoylation; D025801:Ubiquitin / Q000737:chemistry; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D025801:Ubiquitin; D051844:alpha-Synuclein; C496126:PLK2 protein, human; D017346:Protein Serine-Threonine Kinases; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human; D046988:Proteasome Endopeptidase Complex; D008239:Lysine
keywords: Autophagy; Post-translational Modification; Proteasome; Yeast; α-Synuclein