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. The phenotypes were corrected by modulating the lysosomal calcium channel TRPML1 using the drug ML-SA1. We performed RNA-sequencing in control and SPG11 organoids, either untreated or treated with ML-SA1 to identify pathways linking lysosomal dysfunction to proliferation of neural progenitor cells