Fig. 8.

Fig. 8.

Schematic of the proposed sequence of events driving disease progression in the combined saposin deficiency zebrafish model. Increased tnfb and il1b expression is detected at ∼22 dpf in the psap^−/− brain, followed by increased expression of additional neuroinflammatory markers (stat2, stat3, socs1a, nfkbiaa, cd45 and cd68) and loss of myelin (reduced mbpa) at ∼1 mpf; these pathologies worsen over time, preceding loss of neuronal markers (gfap, rbfox3a) and dysregulated mTORC1 signaling at ∼4 mpf, fairly rapid onset of cachexia and locomotion impairment within 2 weeks around the 4-mpf time point, and death of all psap^−/− fish by 5 mpf. Knockout of acid sphingomyelinase (smpd1) in psap^−/− zebrafish leads to a modest increase in lifespan via yet to be investigated mechanisms.