Tyrosine and serine phosphorylation of α-synuclein have opposing effects on neurotoxicity and soluble oligomer formation

Abstract

Mutations in the neuronal protein α-synuclein cause familial Parkinson disease. Phosphorylation of α-synuclein at serine 129 is prominent in Parkinson disease and influences α-synuclein neurotoxicity. Here we report that α-synuclein is also phosphorylated at tyrosine 125 in transgenic Drosophila expressing wildtype human α-synuclein and that this tyrosine phosphorylation protects from α-synuclein neurotoxicity in a Drosophila model of Parkinson disease. Western blot analysis of fly brain homogenates showed that levels of soluble oligomeric species of α-synuclein were increased by phosphorylation at serine 129 and decreased by tyrosine 125 phosphorylation. Tyrosine 125 phosphorylation diminished during the normal aging process in both humans and flies. Notably, cortical tissue from patients with the Parkinson disease-related synucleinopathy dementia with Lewy bodies showed less phosphorylation at tyrosine 125. Our findings suggest that α-synuclein neurotoxicity in Parkinson disease and related synucleinopathies may result from an imbalance between the detrimental, oligomer-promoting effect of serine 129 phosphorylation and a neuroprotective action of tyrosine 125 phosphorylation that inhibits toxic oligomer formation.

Effects of Serine 129 Phosphorylation on α-Synuclein Aggregation, Membrane Association, and Internalization

“…Finally, the use of ␣-syn S129A or S129D mutants to either prevent or mimic phosphorylation in various in vivo models has also yielded conflicting results. Co-expression of S129A ␣-syn in flies rescued the neuronal loss induced by WT ␣-syn expression, and correspondingly, S129D ␣-syn was associated with increased pathology (39,44,47,49,50). However, contrary relationships were observed in other models, including yeast, mammalian cells, Caenorhabditis elegans, and rodents (51-53), and no phenotype was detected in ␣-syn-deficient mice expressing either S129A or S129D transgenes (54).…”

One-pot total chemical synthesis of human α-synuclein

“…Moreover, a-syn can be modified at multiple sites at the same time, suggesting crosstalk between different PTMs. 9 Investigating such cross-talk requires methodologies that allow the simultaneous introduction of multiple modifications in different regions of the protein. Total chemical synthesis of proteins offers unlimited versatility regarding the type, number, and localization of unnatural aminoacids to be introduced.…”

Phosphorylation as Conformational Switch from the Native to Amyloid State: Trp-Cage as a Protein Aggregation Model

“…[9][10][11][12] There is increasing evidence that abnormal-or hyperphosphorylation might be the driving force in the intracellular aggregation of tau protein 13 , α-synuclein [14][15][16][17][18][19][20] and amyloid-β peptide. [21][22][23][24][25] The phosphorylation at specific Ser or Thr residues might promote the nucleation-dependent oligomerization and thus aggregation of these proteins by increasing the β-sheet character of the modified sequences.…”