ArticleNeurobiology of disease2018
DEPDC5 and NPRL3 modulate cell size, filopodial outgrowth, and localization of mTOR in neural progenitor cells and neurons.
Article in Neurobiology of disease, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 41 citations in OpenAlex.
- Clinical and Genetic Characterization of Inherited NPRL3 Splice Variants in Two Patients With Epilepsy.Molecular genetics & genomic medicine · 2026Article
- Review
- The role of genetic testing in evaluating surgical outcomes for pediatric focal cortical dysplasia associated with NPRL3 variant.Epilepsy & behavior reports · 2025Article
- Emerging Role of Tripartite Synaptic Transmission in the Pathomechanism of Autosomal-Dominant Sleep-Related Hypermotor Epilepsy.International journal of molecular sciences · 2025Review
- Phenotypic and genotypic characterization of NPRL3-related epilepsy: Two case reports and literature review.Epilepsia open · 2024Review
- Pathogenic genes implicated in sleep-related hypermotor epilepsy: a research progress update.Frontiers in neurology · 2024Review
- Neurophysiological assessment of cortical activity in DEPDC5- and NPRL3-related epileptic mTORopathies.Orphanet journal of rare diseases · 2023Article
- The clinical features of familial focal epilepsy with variable foci and NPRL3 gene variant.PloS one · 2023Article
- NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination and seizure threshold.Brain : a journal of neurology · 2022Article
- DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting.Cell reports · 2022Article
- Rare CACNA1H and RELN variants interact through mTORC1 pathway in oligogenic autism spectrum disorder.Translational psychiatry · 2022Article
- Increased glycine contributes to synaptic dysfunction and early mortality in Nprl2 seizure model.iScience · 2022Article
- Dorsal telencephalon-specific Nprl2- and Nprl3-knockout mice: novel mouse models for GATORopathy.Human molecular genetics · 2022Article
- Heterogeneity and excitability of BRAFV600E-induced tumors is determined by Akt/mTOR-signaling state and Trp53-loss.Neuro-oncology · 2022Article
- The roles of KLHL family members in human cancers.American journal of cancer research · 2022Review
- Identification of two rareFrontiers in genetics · 2022Article
- Review
- Simvastatin Enhances Muscle Regeneration Through Autophagic Defect-Mediated Inflammation and mTOR Activation in G93ASOD1 Mice.Molecular neurobiology · 2021Article
- Widespread labeling and genomic editing of the fetal central nervous system byDevelopment (Cambridge, England) · 2021Article
- A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci.Frontiers in genetics · 2021Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
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Abstract
Mutations in DEPDC5 and NPRL3 subunits of GATOR1, a modulator of mechanistic target of rapamycin (mTOR), are linked to malformations of cortical development (MCD). Brain specimens from these individuals reveal abnormal cortical lamination, altered cell morphology, and hyperphosphorylation of ribosomal S6 protein (PS6), a marker for mTOR activation. While numerous studies have examined GATOR1 subunit function in non-neuronal cell lines, few have directly assessed loss of GATOR1 subunit function in neuronal cell types. We hypothesized that DEPDC5 or NPRL3 shRNA-mediated knockdown (DEPDC5/NPRL3 KD) leads to inappropriate functional activation of mTOR and mTOR-dependent alterations in neuronal morphology. Neuronal size was determined in human specimens harboring DEPDC5 or NPRL3 mutations resected for epilepsy treatment. DEPDC5/NPRL3 KD effects on cell size, filopodial extension, subcellular mTOR complex 1 (mTORC1) localization, and mTORC1 activation during nutrient deprivation were assayed in mouse neuroblastoma cells (N2aC) and mouse subventricular zone derived neural progenitor cells (mNPCs). mTORC1-dependent effects of DEPDC5/NPRL3 KD were determined using the mTOR inhibitor rapamycin. Changes in mTOR subcellular localization and mTORC1 pathway activation following DEPDC5/NPRL3 KD were determined by examining the proximity of mTOR to the lysosomal surface during amino acid starvation. Neurons exhibiting PS6 immunoreactivity (Ser 235/236) in human specimens were 1.5× larger than neurons in post-mortem control samples. DEPDC5/NPRL3 KD caused mTORC1, but not mTORC2, hyperactivation, soma enlargement, and increased filopodia in N2aC and mNPCs compared with wildtype cells. DEPDC5/NPRL3 KD led to inappropriate mTOR localization at the lysosome along with constitutive mTOR activation following amino acid deprivation. DEPDC5/NPRL3 KD effects on morphology and functional mTOR activation were reversed by rapamycin. mTOR-dependent effects of DEPDC5/NPRL3 KD on morphology and subcellular localization of mTOR in neurons suggests that loss-of-function in GATOR1 subunits may play a role in MCD formation during fetal brain development.
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