ELP1 splicing correction reverses proprioceptive sensory loss in familial dysautonomia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA521159 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8539660_1.fastq.gz | Fastqsanger.gz | |||
| SRR8539660_2.fastq.gz | Fastqsanger.gz | |||
| SRR8539661_1.fastq.gz | Fastqsanger.gz | |||
| SRR8539661_2.fastq.gz | Fastqsanger.gz | |||
| SRR8539662_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
Similar Datasets
Project description:Familial dysautonomia (FD) is a recessive neurodegenerative disease caused by a splice mutation in Elongator complex protein 1 (ELP1, also known as IKBKAP) which leads to variable skipping of exon 20 and to a drastic reduction of ELP1 levels in the nervous system. Clinically, many of the debilitating aspects of the disease are related to a progressive loss of proprioception, which leads to severe gait ataxia, spinal deformities and respiratory insufficiency due to neuromuscular incoordination. There is currently no effective treatment for FD and the disease is ultimately fatal. Development of a drug that targets the underlying molecular defect provides hope that the drastic peripheral neurodegeneration characteristic of FD can be halted. We demonstrate herein that the FD mouse, TgFD9; IkbkapΔ20/flox, recapitulates the proprioceptive impairment observed in individuals with FD, and we provide the in vivo evidence that postnatal correction of mutant ELP1 splicing promoted by the small molecule kinetin can rescue neurological phenotypes in FD. Daily administration of kinetin starting at birth improves sensory-motor coordination and prevents the onset of spinal abnormalities by stopping the loss of proprioceptive neurons. These phenotypic improvements correlate with increased levels of full length ELP1 mRNA and protein in multiple tissues including the peripheral nervous system (PNS). Our results show that postnatal correction of the underlying ELP1 splicing defect can rescue devastating disease phenotypes and is therefore a viable therapeutic approach for persons with FD.
2019-03-21 | GSE126155 | GEO
Project description:Familial dysautonomia (FD) is a recessive neurodegenerative disease caused by a splice mutation in Elongator complex protein 1 (ELP1, also known as IKBKAP); this mutation leads to variable skipping of exon 20 and to a drastic reduction of ELP1 in the nervous system. Clinically, many of the debilitating aspects of the disease are related to a progressive loss of proprioception; this loss leads to severe gait ataxia, spinal deformities, and respiratory insufficiency due to neuromuscular incoordination. There is currently no effective treatment for FD, and the disease is ultimately fatal. The development of a drug that targets the underlying molecular defect provides hope that the drastic peripheral neurodegeneration characteristic of FD can be halted. We demonstrate herein that the FD mouse TgFD9;Ikbkap?20/flox recapitulates the proprioceptive impairment observed in individuals with FD, and we provide the in vivo evidence that postnatal correction, promoted by the small molecule kinetin, of the mutant ELP1 splicing can rescue neurological phenotypes in FD. Daily administration of kinetin starting at birth improves sensory-motor coordination and prevents the onset of spinal abnormalities by stopping the loss of proprioceptive neurons. These phenotypic improvements correlate with increased amounts of full-length ELP1 mRNA and protein in multiple tissues, including in the peripheral nervous system (PNS). Our results show that postnatal correction of the underlying ELP1 splicing defect can rescue devastating disease phenotypes and is therefore a viable therapeutic approach for persons with FD.
| S-EPMC6451698 | biostudies-literature
Project description:Familial Dysautonomia (FD) is a rare recessive neurodevelopmental disease caused by a splice site mutation in the Elongator acetyltransferase complex subunit 1 (ELP1) leading to tissue-specific skipping of exon 20 and reduction of the ELP1 protein, distinctly in the central nervous system (CNS) and peripheral nervous system (PNS). Here we performed a transcriptome-wide study to dissect the molecular mechanisms underlying FD in specific neuronal tissues from the FD phenotypic mouse which expresses human ELP1, including the dorsal root ganglion (DRG), trigeminal ganglion (TG), medulla (MED), cortex, and spinal cord (SC). We focused our analyses on differentially expressed genes (DEGs) representing the most dominant transcriptomic alterations; and on genes in co-expression modules that are highly correlated with full-length ELP1 expression (ELP1 dose-responsive genes). We identified higher number of DEGs (342) in the PNS (DRG, TG) as compared to the CNS (MED, SC, Cortex) (143). ELP1 dose-responsive genes are only found in DRG, TG, and MED, not in Cortex or SC, tissues. Gene Ontology analyses of both DEGs and ELP1-dose-responsive genes highlight the regulation of neurotransmitters. The transcriptome-wide signals were highly convergent between PNS tissues (DRG and TG) but not among CNS tissues. Those convergent genes were enriched for known protein-protein interactions and cell type-specific markers defining myelinated neurons and peptidergic nociceptors. Our findings support the involvement of specific neuronal subtypes underlying the PNS phenotypes in FD. Our study comprehensively investigates transcriptome-wide alterations in FD neuronal tissues and identifies the functional dysregulations in the peripheral nervous system contributing to disease.
2023-09-28 | GSE230867 | GEO
Project description:Familial dysautonomia (FD) is a rare genetic neurologic disorder caused by impaired neuronal development and progressive degeneration of both the peripheral and central nervous systems. FD is monogenic, with >99.4% of patients sharing an identical point mutation in the elongator acetyltransferase complex subunit 1 (ELP1) gene, providing a relatively simple genetic background in which to identify modifiable factors that influence pathology. Gastrointestinal symptoms and metabolic deficits are common among FD patients, which supports the hypothesis that the gut microbiome and metabolome are altered and dysfunctional compared to healthy individuals. Here we show significant differences in gut microbiome composition (16 S rRNA gene sequencing of stool samples) and NMR-based stool and serum metabolomes between a cohort of FD patients (~14% of patients worldwide) and their cohabitating, healthy relatives. We show that key observations in human subjects are recapitulated in a neuron-specific Elp1-deficient mouse model, and that cohousing mutant and littermate control mice ameliorates gut microbiome dysbiosis, improves deficits in gut transit, and reduces disease severity. Our results provide evidence that neurologic deficits in FD alter the structure and function of the gut microbiome, which shifts overall host metabolism to perpetuate further neurodegeneration.
2022-12-06 | MTBLS5138 | MetaboLights
Project description:Familial Dysautonomia (FD; OMIM #223900) is both a developmental and progressive autosomal recessive neurodegenerative disorder that results from a nervous-system reduction in the IKAP/ELP1 protein due to a mutation in a splice acceptor site of the IKBKAP/ELP1 gene. The function of this gene in the nervous system is unresolved. To obviate the embryonic lethality of mice completely null for Ikbkap, we generated conditional knock out (CKO) mouse models for FD that recapitulate hallmarks of the human disease. To derive insight into potential intracellular functions for Ikbkap, we conducted a genome-wide transcriptome analysis of both the peripheral and central nervous systems from Ikbkap CKO mice, and identify over 100 shared misregulated genes that reveal roles for IKAP in several metabolic and signaling pathways in addition to synaptic transmission. Importantly, our data are the first to demonstrate that in the absence of IKAP, neurons undergo intracellular stress that is marked by transcriptional elevations in ATF5, p53, and several CREB target genes, as well as an increase in reactive oxygen species. These data will aid in the identification of common upstream and downstream targets for therapeutics for preventing the progressive demise of neurons in FD and potentially other neuropathies.
2020-04-30 | GSE80107 | GEO
Project description:We have generated expression profiles of induced pluripotent stem cells (iPSCs) and iPSC-derived neural crest populations from Familial Dysautonomia patients. These profiles were compared to a normal iPSC line that does not harbor the IKBKAP mutation.
2016-10-25 | GSE67073 | GEO
Project description:Investigate IKAP importance in the development of neuronal cells, in order to understand Familial dysautonomia phenotype.
2011-01-06 | GSE26458 | GEO
Project description:Exploration of transcriptome expression in 5 control and 4 familial dysautonomia (FD) human olfactory ecto-mesenchymal stem cells (hOE-MSCs) at very early (P1 and P2) and later (P5 and P9) cell passages.
2011-01-01 | E-MTAB-281 | biostudies-arrayexpress
Project description:The peripheral nervous system (PNS) is essential for proper body function. A high percentage of the world’s population suffers nerve degeneration or peripheral nerve damage. Despite this, there are major gaps in the knowledge of human PNS development and degeneration and therefore, there are no available treatments. Familial Dysautonomia (FD) is a devastating disorder caused by a homozygous point mutation in the gene ELP1. FD specifically affects the development and causes degeneration of the PNS. We previously employed patient-derived induced pluripotent stem cells (iPSCs) to show that peripheral sensory neurons (SNs) recapitulate the developmental and neurodegenerative defects observed in FD. Here, we conducted a chemical screen to identify compounds that rescue the SN differentiation inefficiency in FD. We identified that genipin restores neural crest and SN development in patient derived iPSCs and in two mouse models of FD. Additionally, genipin prevented FD degeneration in SNs derived from patients with FD, suggesting that it could be used to ameliorate neurodegeneration. Moreover, genipin crosslinked the extracellular matrix (ECM), increased the stiffness of the ECM, reorganized the actin cytoskeleton, and promoted transcription of YAP-dependent genes. Finally, genipin enhanced axon regeneration in healthy sensory and sympathetic neurons (part of the PNS), and in prefrontal cortical neurons (part of the central nervous system), in in vitro axotomy models. Our results suggest that genipin has the potential to treat FD-related neurodevelopmental and neurodegenerative phenotypes, and to enhance neuronal regeneration of healthy neurons after injury. Moreover, this suggests that the ECM can be targeted to treat FD.
2024-11-20 | GSE265932 | GEO
Project description:We have generated expression profiles of induced pluripotent stem cells (iPSCs) and iPSC-derived neural crest populations from Familial Dysautonomia patients. These profiles were compared to a normal iPSC line that does not harbor the IKBKAP mutation. All cell types were differentiated from patient derived iPSCs. Bulk iPSCs were harvested for RNA and the neural crest populations were sorted on day 18 for p75/HNK1 before RNA isolation.
2016-10-25 | E-GEOD-67073 | biostudies-arrayexpress