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Interplay between sumoylation and phosphorylation for protection against α-synuclein inclusions

Lookup NU author(s): Professor Tiago OuteiroORCiD


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© 2014 by The American Society for Biochemistry and Molecular Biology, Inc. 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 autophagymediated aggregate clearance.Adefect 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.

Publication metadata

Author(s): Shahpasandzadeh H, Popova B, Kleinknecht A, Fraser PE, Outeiro TF, Braus GH

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2014

Volume: 289

Issue: 45

Pages: 31224-31240

Print publication date: 07/11/2014

Online publication date: 17/09/2014

Acceptance date: 01/01/1900

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology Inc.


DOI: 10.1074/jbc.M114.559237

PubMed id: 25231978


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