Discovery of S1P/SPHK1 dysregulation in Parkinson's disease and its role in pathological α-synuclein-induced neurodegeneration

Parkinson's disease (PD) manifests a significant lipidopathy, marked by an enrichment of risk genes involved in sphingolipid metabolism. Sphingolipids are master regulators of cell fate, with sphingosine-1-phosphate (S1P) acting as a key signaling mediator in immunology and vascular biology. However, the fluctuation of S1P metabolism in PD and its role in synucleinopathy-induced neurodegeneration remain poorly understood. In this study, we discovered a 16-fold increase in cerebrospinal fluid (CSF) S1P levels synthesized by sphingosine kinase 1 (SPHK1) in PD patients compared to controls, accompanied by a reduction in sphingosine levels. Similarly, elevated S1P levels are observed in the striatum and midbrain of the α-synuclein preformed fibrils (α-syn PFFs)-induced mouse model of sporadic PD, with Sphk1 exhibiting the most pronounced upregulation among genes categorized under the “sphingosine metabolic process”, while Sphk2 expression remains unchanged. The increase of S1P levels is associated with the selective modulation of SPHK1 in microglia responding to pathological α-synuclein. Of note, α-syn PFFs treatment increases Sphk1 expression and activates SPHK1 in microglia. SPHK1 serves as a key contributor to pathologic α-syn-induced microglial activation via S1Pmediated NF-κB signaling. Knockdown of microglial Sphk1 alleviated neurodegenerative pathology in α-syn PFFs mice alleviates their neuropathological changes. Similarly, inhibition of SPHK1 with PF543 ameliorates PD-like neuropathological abnormalities in hA53T α-synuclein transgenic mice. These findings support a key role of S1P in the pathogenesis of PD linked to pathological α-synuclein.