Phosphorylation of a-synuclein at T64 results in distinct oligomers and exerts toxicity in models of Parkinson's disease

a-Synuclein accumulates in Lewy bodies, and this accumulation is a pathological hallmark of Parkinson's disease (PD). Previous studies have indicated a causal role of a-synuclein in the pathogenesis of PD. However, the molecular and cellular mechanisms of a-synuclein toxicity remain elusive. Here, we describe a novel phosphorylation site of a-synuclein at T64 and the detailed characteristics of this post-translational modification. T64 phosphorylation was enhanced in both PD models and human PD brains. T64D phosphomimetic mutation led to distinct oligomer formation, and the structure of the oligomer was similar to that of a-synuclein oligomer with A53T mutation. Such phosphomimetic mutation induced mitochondrial dysfunction, lysosomal disorder, and cell death in cells and neurodegeneration in vivo, indicating a pathogenic role of a-synuclein phosphorylation at T64 in PD.

Automated summary

This study found that phosphorylation of a-Synuclein at T64 was increased in both Parkinson's disease models and human PD brains. The T64D phosphomimetic mutation led to the formation of a-Synuclein oligomers with a similar structure to those with the A53T mutation, and it induced mitochondrial dysfunction, lysosomal disorder, cell death, and neurodegeneration. These findings suggest a pathogenic role of a-Synuclein phosphorylation at T64 in Parkinson's disease.