Abstract
Parkinson´s disease (PD) is characterized by the presence of proteinaceous inclusions called Lewy bodies that are mainly composed of α-synuclein (αSyn). Elevated levels of oxidative or nitrative stresses have been implicated in αSyn related toxicity. Phosphorylation of αSyn 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. αSyn 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 αSyn cytotoxicity and aggregation. Analysis of tyrosine residues involved in nitration and crosslinking revealed that the C-terminus, rather than the N-terminus of αSyn, is modified by nitration and di-tyrosine formation. The nitration level of wild-type αSyn was higher compared to that of A30P mutant that is non-toxic in yeast. A30P formed more dimers than wild-type αSyn, 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 αSyn. Yhb1 protected yeast from A30P-induced mitochondrial fragmentation and peroxynitrite-induced nitrative stress. Strikingly, overexpression of neuroglobin, the human homolog of YHB1, protected against αSyn inclusion formation in mammalian cells. In total, our data suggest that C-terminal Y133 plays a major role in αSyn 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 αSyn di-tyrosine dimers. Our findings uncover a complex interplay between S129 phosphorylation and C-terminal tyrosine modifications of αSyn that likely participates in PD pathology.
Highlights
Parkinsons disease (PD) is one of the most common neurodegenerative diseases and affects about 1% of the population older than 60 years [1]
Human αSyn mimics the disease pathology in yeast resulting in cytotoxicity and aggregate formation. αSyn is abundantly phosphorylated at serine serine 129 (S129) and possesses four tyrosines (Y39, Y125, Y133, and Y136) that can be posttranslationally modified by nitration or phosphorylation
The Y133 residue, which can be either phosphorylated or nitrated, determines whether S129 is protectively phosphorylated and αSyn inclusions are cleared. This interplay with S129 phosphorylation demonstrates a dual role for C-terminal tyrosine residues
Summary
Parkinsons disease (PD) is one of the most common neurodegenerative diseases and affects about 1% of the population older than 60 years [1]. Several independent point mutations in the αSyn encoding gene, as well as duplications or triplications of the wild-type αSyn locus, have been found in rare familial inherited forms of PD [12,13,14,15,16,17,18]. This makes αSyn a hallmark protein for PD and other related diseases, which are summarized as synucleinopathies. The nuclear localization of αSyn remains under debate, since conflicting results have been obtained for the existence of αSyn in nuclei of mammalian brain neurons [19,20,21,22,23]. αSyn was reported to be localized in the nucleus of cultured neurons, where it may impair histone acetylation and thereby promote neurotoxicity [24, 25]. αSyn is involved in the modulation of synaptic activity through regulation of SNARE-complex assembly of presynaptic vesicles, regulation of neurotransmitter release, regulation of cell differentiation and phospholipid metabolism [26,27,28,29,30,31]
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