Physiological roles of α-synuclein serine-129 phosphorylation – not an oxymoron.

There is growing evidence that in the absence of pathology, serine-129 phosphorylation of α-synuclein (αS) serves the purpose of fine-tuning the synaptic function of αS. We posit that pS129 has a dual role in health and disease: a physiological role in regulating αS biology, and a pathological role related to the deposition of insoluble αS into Lewy bodies. We further propose that there is no direct conversion of physiological to pathological pS129. Instead, physiological pS129 is driven by a pathway that involves neuronal activity, calcium, calcineurin, polo-like kinase 2 (Plk2), and protein phosphatase 2A (PP2A), and is readily reversible. Pathological pS129 likely accumulates because aggregated αS is easier for Plk2 to phosphorylate and/or more difficult for PP2A to dephosphorylate than native αS. α-Synuclein (αS) is an abundant presynaptic protein that regulates neurotransmission. It is also a key protein implicated in a broad class of neurodegenerative disorders termed synucleinopathies, including Parkinson's disease (PD) and Lewy body dementia (LBD). Pathological αS deposits in these diseases, Lewy bodies (LBs)/neurites (LNs), contain about 90% of αS in its phospho-serine129 (pS129) form. Therefore, pS129 is widely used as a surrogate marker of pathology. However, recent findings demonstrate that pS129 is also physiologically triggered by neuronal activity to positively regulate synaptic transmission. In this opinion article, we contrast the literature on pathological and physiological pS129, with a special focus on the latter. We emphasize that pS129 is ambiguous and knowledge about the context is necessary to correctly interpret changes in pS129. [ABSTRACT FROM AUTHOR]