α-Synuclein disrupts stress signaling by inhibiting polo-like kinase Cdc5/Plk2

Wang, Shaoxiao; Xu, Baoshan; Liou, Liang-Chun; Ren, Qun; Huang, Shile; Luo, Yan; Zhang, Zhaojie; Witt, Stephan N.

doi:10.1073/pnas.1206286109

Cited by 40 publications

(37 citation statements)

References 29 publications

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“…Contrary to our observation, their data showed that deletion of the 11 first amino acids of ␣-syn is sufficient to alter the interaction and the phosphorylation of ␣-syn by CDC5, the yeast ortholog of human PLK2 (21). This apparent discrepancy could be due to the fact that although orthologs, the protein structures of CDC5 and PLK2 are different (only 30% homology; UniProt), which may implicate distinct protein regions and conformations for the interaction with ␣-syn.…”

Section: Discussioncontrasting

confidence: 54%

“…Previous work by Wang et al (21) studied ␣-syn and PLK2 interaction in yeast cells. Contrary to our observation, their data showed that deletion of the 11 first amino acids of ␣-syn is sufficient to alter the interaction and the phosphorylation of ␣-syn by CDC5, the yeast ortholog of human PLK2 (21).…”

Section: Discussionmentioning

confidence: 99%

“…A recent work by Wang et al 21 reported that the first 11 amino acids (2-11) of ␣-syn structure are required for its interaction and phosphorylation by CDC5, the yeast ortholog of human PLK2, emphasizing the role of ␣-syn N-terminal segment in the interaction between the two proteins. To assess the importance of this region on ␣-syn interaction with PLK2, phosphorylation, and degradation in mammalian cell lines, we overexpressed PLK2 either with the truncated form of ␣-syn missing the first 11 amino acids (␣-syn ⌬2-11) or with the construct missing the entire amphipathic N-terminal region (␣-syn ⌬2-60).…”

Section: Plk2 and Plk3 Regulate ␣-Syn Protein Levels In A Ser-129mentioning

confidence: 99%

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Dissecting the Molecular Pathway Involved in PLK2 Kinase-mediated α-Synuclein-selective Autophagic Degradation

Dahmene

Bérard

Oueslati

2017

Journal of Biological Chemistry

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Edited by Roger J. ColbranIncreasing lines of evidence support the causal link between ␣-synuclein (␣-syn) accumulation in the brain and Parkinson's disease (PD) pathogenesis. Therefore, lowering ␣-syn protein levels may represent a viable therapeutic strategy for the treatment of PD and related disorders. We recently described a novel selective ␣-syn degradation pathway, catalyzed by the activity of the Polo-like kinase 2 (PLK2), capable of reducing ␣-syn protein expression and suppressing its toxicity in vivo. However, the exact molecular mechanisms underlying this degradation route remain elusive. In the present study we report that among PLK family members, PLK3 is also able to catalyze ␣-syn phosphorylation and degradation in living cells. Using pharmacological and genetic approaches, we confirmed the implication of the macroautophagy on PLK2-mediated ␣-syn turnover, and our observations suggest a concomitant co-degradation of these two proteins. Moreover, we showed that the N-terminal region of ␣-syn is important for PLK2-mediated ␣-syn phosphorylation and degradation and is implicated in the physical interaction between the two proteins. We also demonstrated that PLK2 polyubiquitination is important for PLK2⅐␣-syn protein complex degradation, and we hypothesize that this post-translational modification may act as a signal for the selective recognition by the macroautophagy machinery. Finally, we observed that the PD-linked mutation E46K enhances PLK2-mediated ␣-syn degradation, suggesting that this mutated form is a bona fide substrate of this degradation pathway. In conclusion, our study provides a detailed description of the new degradation route of ␣-syn and offers new opportunities for the development of therapeutic strategies aiming to reduce ␣-syn protein accumulation and toxicity. Parkinson's disease (PD)2 is a neurodegenerative disorder characterized by the progressive loss of vulnerable neuronal populations in the brain and the accumulation of proteinaceous intraneuronal inclusions called Lewy bodies (1, 2). These inclusions mainly consist of a presynaptic protein, ␣-synuclein (␣-syn) (3-5). Converging lines of evidence from neuropathological studies and experimental models support the central role of ␣-syn aggregation and toxicity in the pathogenesis of PD (3, 6). This ␣-syn abnormal accumulation is in part triggered by its gene duplications/triplications or by the impairment of its degradation (3, 6). Therefore, enhancing ␣-syn elimination may represent a viable therapeutic strategy for the treatment of PD and related disorders.However, the question on how ␣-syn is eliminated in vivo has yielded controversial results (7). Although some studies reported specific elimination of the monomeric and fibrillar ␣-syn forms by the ubiquitin-proteasome system (8 -10), others reported the degradation of this protein via the autophagy-lysosomal pathway, notably the chaperone-mediated autophagy (10 -12). This controversy and the lack of known selective routes for ␣-syn elimination precluded the development ...

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Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Plk2 and Plk3 Regulate ␣-Syn Protein Levels In A Ser-129mentioning

confidence: 99%

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Dissecting the Molecular Pathway Involved in PLK2 Kinase-mediated α-Synuclein-selective Autophagic Degradation

Dahmene

Bérard

Oueslati

2017

Journal of Biological Chemistry

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“…Preparation of yeast cell lysates, SDS/PAGE, and Western blot analysis was carried out as described previously (31). Protein concentrations were determined using a bicinchoninic acid assay (Pierce).…”

Section: Methodsmentioning

confidence: 99%

Phosphatidylethanolamine deficiency disrupts α-synuclein homeostasis in yeast and worm models of Parkinson disease

Wang¹,

Zhang

Liou

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance We tested the hypothesis that a form of mitochondrial dysfunction alters the homeostasis of the cytosolic Parkinson disease (PD)-associated protein α-synuclein (α-syn). Using yeast and worm models of PD, we show that low levels of phosphatidylethanolamine (PE), caused by the depletion of mitochondrial phosphatidylserine decarboxylase (psd), lead to decreased respiration, endoplasmic reticulum (ER) stress, high levels of α-syn and cytoplasmic α-syn foci, and slow growth. Ethanolamine, which replenishes PE through the Kennedy pathway, diminished ER stress, decreased the level of α-syn, eliminated foci, and restored growth of psd1 Δ cells to near wild-type levels. A low level of mitochondrial PE disrupts the homeostasis of α-syn and leads to the accumulation of cytoplasmic foci of this protein.

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“…␣Syn can be phosphorylated in yeast by endogenous kinases (55). Several kinase families are reported to phosphorylate ␣Syn at Ser-129 in higher eukaryotes (19 -22, 27, 28, 56 -58).…”

Section: Protective Function Of Sumo Requires Direct Modification Of mentioning

confidence: 99%

Interplay between Sumoylation and Phosphorylation for Protection against α-Synuclein Inclusions

Shahpasandzadeh

Popova

Kleinknecht

et al. 2014

Journal of Biological Chemistry

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Background: Phosphorylation and sumoylation are post-translational modifications of the Parkinson disease protein ␣-synuclein. Results: ␣-Synuclein inclusion clearance is impaired in yeast when sumoylation is inhibited; phosphorylation of ␣-synuclein can compensate SUMO impairment. Conclusion: Sumoylation stimulates autophagy clearance of ␣-synuclein inclusions, whereas phosphorylation promotes autophagy and proteasome degradation. Significance: A complex molecular post-translational cross-talk is required in yeast to clear toxic inclusions.

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α-Synuclein disrupts stress signaling by inhibiting polo-like kinase Cdc5/Plk2

Cited by 40 publications

References 29 publications

Dissecting the Molecular Pathway Involved in PLK2 Kinase-mediated α-Synuclein-selective Autophagic Degradation

Dissecting the Molecular Pathway Involved in PLK2 Kinase-mediated α-Synuclein-selective Autophagic Degradation

Phosphatidylethanolamine deficiency disrupts α-synuclein homeostasis in yeast and worm models of Parkinson disease

Interplay between Sumoylation and Phosphorylation for Protection against α-Synuclein Inclusions

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