Figure 9
Proposed signaling cascade of sphingoid-base phosphate-induced neurotoxicity. Calpain is the central signaling molecule and mediates sphingoid-base phosphate-induced neuronal apoptosis by activation of ER stress-specific caspase cascade and initiation of cell cycle reactivation. In addition, calpain/CDK5-dependent tau hyperphosphorylation is induced. The metabolic fate of exogenous cimes and S1P in wild-type and S1P-lyase-deficient mice, respectively, was described previously.12 CDK5, cyclin-dependent kinase5; cimes, cis-4-methylsphingosine; cimesP, cis-4-methylsphingosine-phosphate; ER, endoplasmic reticulum; Rb, retinoblastoma protein; SK2; sphingosine-kinase2; Sph, sphingosine; SPP, sphingosine-phosphate phosphatase
