ArticleHuman molecular genetics2015
HD iPSC-derived neural progenitors accumulate in culture and are susceptible to BDNF withdrawal due to glutamate toxicity.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 132 citations in OpenAlex.
- Roles of MAPKs, Including Those Activated by BDNF/TrkB, and Their Contribution in Neurodegenerative Diseases.International journal of molecular sciences · 2026Review
- Brain organoid models of Huntington's disease shift the focus towards neurodevelopment.Disease models & mechanisms · 2025Article
- Article
- Intersecting impact of CAG repeat and huntingtin knockout in stem cell-derived cortical neurons.Neurobiology of disease · 2025Article
- DurableMolecular therapy. Nucleic acids · 2025Article
- Current Development of iPSC-Based Modeling in Neurodegenerative Diseases.International journal of molecular sciences · 2025Review
- Mutant huntingtin exon 1 protein detected in mouse brain with neoepitope antibody: effects of CAG repeat expansion, MutS Homolog 3 silencing and aggregation.Brain communications · 2025Article
- Induced Pluripotent Stem Cells and Organoids in Advancing Neuropathology Research and Therapies.Cells · 2024Review
- How to differentiate induced pluripotent stem cells into sensory neurons for disease modelling: a functional assessment.Stem cell research & therapy · 2024Article
- Rapid and high-purity differentiation of human medium spiny neurons reveals LMNB1 hypofunction and subtype necessity in modeling Huntington's disease.Inflammation and regeneration · 2024Article
- Mutant huntingtin confers cell-autonomous phenotypes on Huntington's disease iPSC-derived microglia.Scientific reports · 2023Article
- Nuclear ERK1/2 signaling potentiation enhances neuroprotection and cognition via Importinα1/KPNA2.EMBO molecular medicine · 2023Article
- Brain-Derived Neurotrophic Factor Dysregulation as an Essential Pathological Feature in Huntington's Disease: Mechanisms and Potential Therapeutics.Biomedicines · 2023Review
- The Use of Stem Cells as a Potential Treatment Method for Selected Neurodegenerative Diseases: Review.Cellular and molecular neurobiology · 2023Review
- Tetracycline-Inducible and Reversible Stable Gene Expression in Human iPSC-Derived Neural Progenitors and in the Postnatal Mouse Brain.Current protocols · 2023Article
- Single-nuclei transcriptome analysis of Huntington disease iPSC and mouse astrocytes implicates maturation and functional deficits.iScience · 2023Article
- Extracellular vesicles improve GABAergic transmission in Huntington's disease iPSC-derived neurons.Theranostics · 2023Article
- Allele-specific silencing of the gain-of-function mutation in Huntington's disease using CRISPR/Cas9.JCI insight · 2022Article
- An insight into the iPSCs-derived two-dimensional culture and three-dimensional organoid models for neurodegenerative disorders.Interface focus · 2022Review
- Chemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington's disease models.Nature communications · 2022Article
16 more citing papers are in PubMed but not listed here.
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16 authors at 5 institutions in 2 countries.
Funding
Abstract
Huntington's disease (HD) is a fatal neurodegenerative disease, caused by expansion of polyglutamine repeats in the Huntingtin gene, with longer expansions leading to earlier ages of onset. The HD iPSC Consortium has recently reported a new in vitro model of HD based on the generation of induced pluripotent stem cells (iPSCs) from HD patients and controls. The current study has furthered the disease in a dish model of HD by generating new non-integrating HD and control iPSC lines. Both HD and control iPSC lines can be efficiently differentiated into neurons/glia; however, the HD-derived cells maintained a significantly greater number of nestin-expressing neural progenitor cells compared with control cells. This cell population showed enhanced vulnerability to brain-derived neurotrophic factor (BDNF) withdrawal in the juvenile-onset HD (JHD) lines, which appeared to be CAG repeat-dependent and mediated by the loss of signaling from the TrkB receptor. It was postulated that this increased death following BDNF withdrawal may be due to glutamate toxicity, as the N-methyl-d-aspartate (NMDA) receptor subunit NR2B was up-regulated in the cultures. Indeed, blocking glutamate signaling, not just through the NMDA but also mGlu and AMPA/Kainate receptors, completely reversed the cell death phenotype. This study suggests that the pathogenesis of JHD may involve in part a population of 'persistent' neural progenitors that are selectively vulnerable to BDNF withdrawal. Similar results were seen in adult hippocampal-derived neural progenitors isolated from the BACHD model mouse. Together, these results provide important insight into HD mechanisms at early developmental time points, which may suggest novel approaches to HD therapeutics.
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