SPHK1 blockade mitigates fibrillar a-synuclein-induced neuropathological burden in Parkinsons disease mice

Parkinsons disease (PD) is the most common form of synucleinopathy and the fastest growing neurodegenerative disorder worldwide. However, no therapy can arrest PD progression. Here we report that the levels of sphingosine-1-phosphate (S1P) in the cerebrospinal fluid of PD patients are 15 times higher than those in controls. Blocking sphingosine kinase 1 (SPHK1) with the inhibitor PF543 rescues neuropathological abnormalities in both the a-synuclein preformed fibrils-induced mouse model of sporadic PD and hA53T a-synuclein transgenic mice. These effects are regulated by the IRE1a-S1P-NF-kB axis in microglia. PD mouse brains show activation of the unfolded protein response (UPR) and an inflammatory phenotype, which are abrogated by PF543. In mouse microglia, a-synuclein fibrils extensively co-localize with the UPR repressor, HSPA5/BiP, causing its dissociation from IRE1a and leading to S1P-dependent NF-kB activation. Our findings suggest that the IRE1a-S1P-NF-kB cascade governs the pathogenic activity of microglia induced by fibrillar a-synuclein, highlighting SPHK1 as a promising therapeutic target for PD.