SPG11 models reveal lysosomal calcium regulation 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. Pharmacological modulation of 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.
Related
- Arcuate kisspeptin neurons display two types of calcium events: Regulation by sex, gonads, and senktide
- Dilution‐Driven Regulation of Biostimulatory Signaling in Calcium Hydroxylapatite–PRGF Systems: Implications for Early Dermal Remodeling
- Network Pharmacology-Guided Identification of Orientin from Passiflora incarnata Reveals Neuroprotective Effects Against Glutamate-Induced Excitotoxicity Through Regulation of Calcium Homeostasis.
- Timed secreted proteomes reveal regulation of hepatokines by the liver circadian clock
- Heterogeneous and conserved radiation responses reveal FOXM1-dependent regulation of microcephaly genes in glioblastoma
BibTeX
@article{samaroo2026spg11,
title = {{SPG11 models reveal lysosomal calcium regulation of neural progenitor proliferation}},
author = {Dominic Samaroo and Margaux Cauhapé and Léa Bernachot and Salomé Moulière and Frédéric Darios},
journal = {Neurobiology of Disease},
year = {2026},
month = oct,
doi = {10.1016/j.nbd.2026.107423},
url = {https://hal.sorbonne-universite.fr/hal-05773021v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SPG11 models reveal lysosomal calcium regulation of neural progenitor proliferation
AU - Dominic Samaroo
AU - Margaux Cauhapé
AU - Léa Bernachot
AU - Salomé Moulière
AU - Frédéric Darios
PY - 2026
DA - 2026/10/01
JO - Neurobiology of Disease
DO - 10.1016/j.nbd.2026.107423
UR - https://hal.sorbonne-universite.fr/hal-05773021v1
AB - 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. Pharmacological modulation of 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.
SN - 0969-9961
SN - 1095-953X
ER -