Dynamic physiological α-synuclein S129 phosphorylation is driven by neuronal activity.

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Alpha-synuclein phosphorylated at Serine129 (pS129) is a key marker in synucleinopathies like Parkinson's disease.
• The physiological function of pS129 has remained largely undefined.

Purpose of the Study:

• To investigate the physiological role of alpha-synuclein phosphorylation at Serine129 (pS129).
• To determine if pS129 regulates neuronal activity and neurotransmission.

Main Methods:

• Utilized cultured neurons and mouse models to study activity-dependent alpha-synuclein phosphorylation.
• Employed patch clamping electrophysiology and generated S129A knock-in mice.
• Investigated the kinase/phosphatase pathways involved in pS129 regulation.

Main Results:

• Neuronal activity robustly increases pS129 levels in a reversible, non-cytotoxic manner.
• pS129 accumulates at presynaptic boutons and fine-tunes excitatory/inhibitory neuronal currents.
• S129A knock-in mice exhibit impaired hippocampal plasticity, indicating a role in synaptic function.

Conclusions:

• pS129 is a physiological regulator of neuronal activity and neurotransmission.
• The findings provide new insights into alpha-synuclein's function beyond disease pathology.
• pS129's role adds complexity to its interpretation as solely a synucleinopathy biomarker.