SPG11 organoids reveal lysosomal calcium regulation of neural progenitor proliferation

Lysosome dysfunction has been widely implicated in many models of neurodegeneration, but much less is understood of its involvement during brain development in health and disease. Hereditary spastic paraplegia caused by mutations in the SPG11 gene is a neurodevelopmental and neurodegenerative disorder characterized by lysosome dysfunction. We identify here lysosomal accumulation of calcium in SPG11 cellular models. We show that alteration of lysosomal calcium reduced proliferation of neural progenitor cells and diminished apical tight junctions in early human cortical development, modeled using organoids derived from induced pluripotent stem cells. RNA sequencing analysis revealed that these phenotypes in SPG11 organoids are caused by hypoactivation of mTOR signaling. The latter is a consequence of lysosomal recruitment of the enzyme PI4K2A (phosphatidylinositol 4-kinase type 2 alpha) resulting in higher levels of its product PI(4)P (phosphatidylinositol-4- phosphate), a described regulator of the mTOR pathway. We observed a successful correction of all phenotypes by modulating the function of the lysosomal calcium channel TRPML1, highlighting the role of lysosomal calcium in signaling during the early phase of cortical development.