Figure 7.

A proposed mechanistic model to be further tested in the future: Release of Ca²⁺ from lysosome is primarily through two Ca²⁺ channels, TRPML1 and TPC2⁴⁵. PI3,5P₂ binds with TRPML1 to activate Ca²⁺ efflux through TRPML1¹⁰. Since PI3,5P₂ is deficient in Fig4−/− cells, lysosomes develop a high level of Ca²⁺. The extra Ca²⁺ in Fig4−/− lysosomes can be released by internal or external signals (speculated from axons or macrophages) to stimulate expression of dedifferentiation molecules like c-Jun, promoting demyelination. Excessive Ca²⁺ could also promote demyelination via other unidentified pathways.