Ser129 Phosphorylation Paradox: Non-phosphorylated α-Synuclein Drives Parkinson' s Disease-like Pathogenesis in Vivo

Accumulation of phosphorylated -synuclein at serine 129 is a hallmark of Parkinsons disease (PD), but its pathogenic role remains controversial. We conducted longitudinal studies using non-phosphorylatable S129A and phosphomimetic S129D -synuclein global knock-in mice. Unexpectedly, the S129A mice--rather than S129D mice--developed reproducible olfactory, motor, and cognitive deficits, dopaminergic dysfunction and neurodegeneration, -synuclein insolubility, and Lewy-like inclusions by 3 to 9 months, with progressive worsening up to 12 months of age. Spatial transcriptomics and electron microscopy revealed mitochondrial, synaptic, and protein ubiquitination abnormalities in the substantia nigra of S129A -synuclein mice. Viral vector-mediated nigral overexpression of S129D--synuclein or systemic administration of an anti--synuclein-aggregation drug partially alleviated the early neurological phenotypes of S129A mice. These results implicate non-phosphorylatable -synuclein as a direct pathogenic driver for PD.