Alpha-synuclein phosphorylation is abundant in the non-synucleinopathy human brain

Phosphorylation of alpha-synuclein at serine 129 (PS129) has been strongly associated with aggregates and implicated in the synucleinopathy disease processes. Recent findings suggest that PS129 is abundant in the non-synucleinopathy mammalian brain, in a brain region-specific and context-dependent manner, raising important questions about the significance of PS129 for synucleinopathy disease processes. Here, we identified and described phosphatase labile physiological PS129 in the mammalian brain using a range of specimens from rodent to human surgically resected temporal lobectomy tissues. Results confirmed phosphatase-sensitive physiological PS129 in the non-synucleinopathy human temporal lobe and hippocampus when the post-mortem interval was eliminated (i.e., surgically resected human samples or perfusion-fixed animal brain). In the non-synucleinopathy mammalian brain, PS129 fluctuated between 2-45% of the total asyn pool in a case-specific and brain region-specific manner. In agreement with previous studies, physiological PS129 was abundantly distributed throughout the layers of the hippocampus and cortex. Physiological PS129 was not observed in PD brain, or non-synucleinopathy specimens of >2h post-mortem interval. Remarkably, in the PD brain, the PS129 to asyn ratio was similar (∼5-40%) to that in the non-synucleinopathy brain. Despite physiological PS129 being associated with neuronal activity, physiological PS129 did not correlate with cFos expression. Conclusions: Physiological PS129 is abundant in the human brain, and apparent pathological enrichment, in part, can be explained by the enzymatic resistance of aggregates and not disease-driven phosphorylation events.