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.

Mutations in the synaptic protein ␣-synuclein cause rare genetic forms of Parkinson's disease. ␣-Synuclein is thought to play a critical role in more common sporadic cases of Parkinson's disease as well because the protein aggregates in the hallmark intraneuronal inclusions of the disorder, Lewy bodies. To test the role of protein aggregation in the pathogenesis of Parkinson's disease, we expressed a form of ␣-synuclein with a deletion of amino acids 71-82 that is unable to aggregate in vitro in a transgenic Drosophila model of the disorder. We found no evidence of large aggregates or oligomeric species of ␣-synuclein in these animals and no loss of tyrosine hydroxylase-positive neurons. We also expressed a truncated form of ␣-synuclein that has enhanced ability to aggregate in vitro. This truncated form of ␣-synuclein showed increased aggregation into large inclusions bodies, increased accumulation of high molecular weight ␣-synuclein species, and demonstrated enhanced neurotoxicity in vivo. Our findings thus support a critical role for aggregation of ␣-synuclein in mediating toxicity to dopaminergic neurons in vivo, although the precise role each aggregated form of ␣-synuclein plays in neurotoxicity remains to be determined.