SPG11 models reveal lysosomal calcium as a regulator of neural progenitor proliferation

Abstract 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 neurodegenerative disorder characterized by lysosome dysfunction, which also presents neurodevelopmental alterations. Using knockout mouse and cortical organoid models derived from induced pluripotent stem cells, we show that lysosome dysfunction caused by SPG11 mutations decreases the proliferation of neural progenitor cells at early stages of cortical development. At the cellular level, SPG11 mutations cause accumulation of calcium in lysosomes, which reduces proliferation of neural progenitor cells and diminishes apical tight junctions. RNA sequencing analysis revealed that these phenotypes in SPG11 organoids are caused by hypoactivation of mammalian target of rapamycin (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. Modulating the function of the lysosomal calcium channel TRPML1 successfully corrected all developmental phenotypes in cortical organoids, highlighting the critical role of lysosomal calcium in signaling during the early phase of cortical development. Competing Interest Statement The authors have declared no competing interest. Footnotes We added data obtained in a Spg11 knockout mouse model (Figure 1, Suppl. Fig. 1) to support the findings in organoid models.