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C-Terminal Tyrosine Residue Modifications Modulate the Protective Phosphorylation of Serine 129 of ?-Synuclein in a Yeast Model of Parkinson's Disease.


ABSTRACT: Parkinson´s disease (PD) is characterized by the presence of proteinaceous inclusions called Lewy bodies that are mainly composed of ?-synuclein (?Syn). Elevated levels of oxidative or nitrative stresses have been implicated in ?Syn related toxicity. Phosphorylation of ?Syn on serine 129 (S129) modulates autophagic clearance of inclusions and is prominently found in Lewy bodies. The neighboring tyrosine residues Y125, Y133 and Y136 are phosphorylation and nitration sites. Using a yeast model of PD, we found that Y133 is required for protective S129 phosphorylation and for S129-independent proteasome clearance. ?Syn can be nitrated and form stable covalent dimers originating from covalent crosslinking of two tyrosine residues. Nitrated tyrosine residues, but not di-tyrosine-crosslinked dimers, contributed to ?Syn cytotoxicity and aggregation. Analysis of tyrosine residues involved in nitration and crosslinking revealed that the C-terminus, rather than the N-terminus of ?Syn, is modified by nitration and di-tyrosine formation. The nitration level of wild-type ?Syn was higher compared to that of A30P mutant that is non-toxic in yeast. A30P formed more dimers than wild-type ?Syn, suggesting that dimer formation represents a cellular detoxification pathway in yeast. Deletion of the yeast flavohemoglobin gene YHB1 resulted in an increase of cellular nitrative stress and cytotoxicity leading to enhanced aggregation of A30P ?Syn. Yhb1 protected yeast from A30P-induced mitochondrial fragmentation and peroxynitrite-induced nitrative stress. Strikingly, overexpression of neuroglobin, the human homolog of YHB1, protected against ?Syn inclusion formation in mammalian cells. In total, our data suggest that C-terminal Y133 plays a major role in ?Syn aggregate clearance by supporting the protective S129 phosphorylation for autophagy and by promoting proteasome clearance. C-terminal tyrosine nitration increases pathogenicity and can only be partially detoxified by ?Syn di-tyrosine dimers. Our findings uncover a complex interplay between S129 phosphorylation and C-terminal tyrosine modifications of ?Syn that likely participates in PD pathology.

SUBMITTER: Kleinknecht A 

PROVIDER: S-EPMC4920419 | BioStudies | 2016-01-01

REPOSITORIES: biostudies

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