ArticleAnnals of neurology2016
GSK3ß-dependent dysregulation of neurodevelopment in SPG11-patient induced pluripotent stem cell model.
Article in Annals of neurology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
What it found
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Who cites it
33 citing papers in PubMed, 46 citations in OpenAlex.
- Neurodevelopmental alterations are key drivers of SPG56.Human molecular genetics · 2026Article
- Neuroaxonal Degeneration as a Converging Mechanism in Motor Neuron Diseases (MNDs): Molecular Insights into RNA Dysregulation and Emerging Therapeutic Targets.International journal of molecular sciences · 2025Review
- Neurodevelopmental Implications Underpinning Hereditary Spastic Paraplegia.CNS neuroscience & therapeutics · 2025Review
- Transcriptomic analysis reinforces the implication of spatacsin in neuroinflammation and neurodevelopment.Scientific reports · 2025Article
- Review
- Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias.International journal of molecular sciences · 2024Review
- Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients.Acta neuropathologica · 2024Article
- Rescue of lysosomal function as therapeutic strategy for SPG15 hereditary spastic paraplegia.Brain : a journal of neurology · 2023Article
- In vitro modelling of human proprioceptive sensory neurons in the neuromuscular system.Scientific reports · 2022Article
- Article
- Exploring Motor Neuron Diseases Using iPSC Platforms.Stem cells (Dayton, Ohio) · 2022Article
- Monitoring Axonal Degeneration in Human Pluripotent Stem Cell Models of Hereditary Spastic Paraplegias.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Single cell morphology distinguishes genotype and drug effect in Hereditary Spastic Paraplegia.Scientific reports · 2021Article
- Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies.Molecular psychiatry · 2021Article
- Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Hereditary Spastic Paraplegia: From Genes, Cells and Networks to Novel Pathways for Drug Discovery.Brain sciences · 2021Review
- Axon-Specific Mitochondrial Pathology in SPG11 Alpha Motor Neurons.Frontiers in neuroscience · 2021Article
- Recent advances in understanding hereditary spastic paraplegias and emerging therapies.Faculty reviews · 2021Review
- Janus-faced spatacsin (SPG11): involvement in neurodevelopment and multisystem neurodegeneration.Brain : a journal of neurology · 2020Review
- Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking.Human molecular genetics · 2020Article
Corrections and comments
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Authors and funding
22 authors at 3 institutions in 2 countries.
Funding
Abstract
objectiveMutations in the spastic paraplegia gene 11 (SPG11), encoding spatacsin, cause the most frequent form of autosomal-recessive complex hereditary spastic paraplegia (HSP) and juvenile-onset amyotrophic lateral sclerosis (ALS5). When SPG11 is mutated, patients frequently present with spastic paraparesis, a thin corpus callosum, and cognitive impairment. We previously delineated a neurodegenerative phenotype in neurons of these patients. In the current study, we recapitulated early developmental phenotypes of SPG11 and outlined their cellular and molecular mechanisms in patient-specific induced pluripotent stem cell (iPSC)-derived cortical neural progenitor cells (NPCs).
methodsWe generated and characterized iPSC-derived NPCs and neurons from 3 SPG11 patients and 2 age-matched controls.
resultsGene expression profiling of SPG11-NPCs revealed widespread transcriptional alterations in neurodevelopmental pathways. These include changes in cell-cycle, neurogenesis, cortical development pathways, in addition to autophagic deficits. More important, the GSK3ß-signaling pathway was found to be dysregulated in SPG11-NPCs. Impaired proliferation of SPG11-NPCs resulted in a significant diminution in the number of neural cells. The decrease in mitotically active SPG11-NPCs was rescued by GSK3 modulation.
interpretationThis iPSC-derived NPC model provides the first evidence for an early neurodevelopmental phenotype in SPG11, with GSK3ß as a potential novel target to reverse the disease phenotype. Ann Neurol 2016;79:826-840.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.