ArticlePloS one2015
Familial Dysautonomia (FD) Human Embryonic Stem Cell Derived PNS Neurons Reveal that Synaptic Vesicular and Neuronal Transport Genes Are Directly or Indirectly Affected by IKBKAP Downregulation.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 25 citations in OpenAlex.
- Impaired Activity-Regulated Proteostasis: A Shared Mechanism in Neurodevelopmental Disorders.Biological psychiatry · 2026Review
- Article
- A Comprehensive NMR Analysis of Serum and Fecal Metabolites in Familial Dysautonomia Patients Reveals Significant Metabolic Perturbations.Metabolites · 2023Article
- Dysregulated proteostasis network in neuronal diseases.Frontiers in cell and developmental biology · 2023Review
- Norepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models.Nature communications · 2022Article
- Loss of Elp1 disrupts trigeminal ganglion neurodevelopment in a model of familial dysautonomia.eLife · 2022Article
- ATP-citrate lyase promotes axonal transport across species.Nature communications · 2021Article
- Retrograde nerve growth factor signaling abnormalities in familial dysautonomia.The Journal of clinical investigation · 2020Article
- Induced pluripotent stem cells for disease modeling, cell therapy and drug discovery in genetic autonomic disorders: a review.Clinical autonomic research : official journal of the Clinical Autonomic Research Society · 2019Review
- Impact of tRNA Modifications and tRNA-Modifying Enzymes on Proteostasis and Human Disease.International journal of molecular sciences · 2018Review
- Retina-specific loss ofDisease models & mechanisms · 2018Article
- Animal and cellular models of familial dysautonomia.Clinical autonomic research : official journal of the Clinical Autonomic Research Society · 2017Review
- BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Phosphatidylserine Ameliorates Neurodegenerative Symptoms and Enhances Axonal Transport in a Mouse Model of Familial Dysautonomia.PLoS genetics · 2016Article
- MicroRNA screening identifies a link between NOVA1 expression and a low level of IKAP in familial dysautonomia.Disease models & mechanisms · 2016Article
- Human neural crest cells contribute to coat pigmentation in interspecies chimeras after in utero injection into mouse embryos.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Familial Dysautonomia: Mechanisms and Models.Genetics and molecular biologyArticle
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A splicing mutation in the IKBKAP gene causes Familial Dysautonomia (FD), affecting the IKAP protein expression levels and proper development and function of the peripheral nervous system (PNS). Here we found new molecular insights for the IKAP role and the impact of the FD mutation in the human PNS lineage by using a novel and unique human embryonic stem cell (hESC) line homozygous to the FD mutation originated by pre implantation genetic diagnosis (PGD) analysis. We found that IKBKAP downregulation during PNS differentiation affects normal migration in FD-hESC derived neural crest cells (NCC) while at later stages the PNS neurons show reduced intracellular colocalization between vesicular proteins and IKAP. Comparative wide transcriptome analysis of FD and WT hESC-derived neurons together with the analysis of human brains from FD and WT 12 weeks old embryos and experimental validation of the results confirmed that synaptic vesicular and neuronal transport genes are directly or indirectly affected by IKBKAP downregulation in FD neurons. Moreover we show that kinetin (a drug that corrects IKBKAP alternative splicing) promotes the recovery of IKAP expression and these IKAP functional associated genes identified in the study. Altogether, these results support the view that IKAP might be a vesicular like protein that might be involved in neuronal transport in hESC derived PNS neurons. This function seems to be mostly affected in FD-hESC derived PNS neurons probably reflecting some PNS neuronal dysfunction observed in FD.
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