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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.
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.
URL: https://doi.org/10.1074/jbc.M114.559237
DOI: 10.1074/jbc.M114.559237
PubMed id: 25231978
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