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RNA-Seq data for dorsal root ganglia of RECTAS-treated ELP1/IKBKAP (IVS20+6T>C) transgenic mice

ABSTRACT: ELP1/IKBKAP IVS20+6T>C is a causal mutation of familial disautonomia. Small molecule compound RECTAS efficiently suppress Exon 20 skipping, caused by this mutation. Its efficacy in vivo was evaluated by RNA-Seq for dorsal root ganglia from HsELP1 (IVS20+6T>C) transgenic mice, following p.o. administration of 0.5% carboxy methyl cellulose (CMC) or RECTAS (300 mg/kgBW).

ORGANISM(S): Mus musculus

PROVIDER: GSE161109 | GEO | 2021/03/10

REPOSITORIES: GEO

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ELP1 splicing correction reverses proprioceptive sensory loss in familial dysautonomia

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.

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RNA-Seq data for dorsal root ganglia of RECTAS-treated ELP1/IKBKAP (IVS20+6T>C) transgenic mice

Project description:RNA-Seq data for dorsal root ganglia of RECTAS-treated ELP1/IKBKAP (IVS20+6T>C) transgenic mice

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Transcriptome analyses of the nervous system of Familial Dysautonomia-model mice identify novel cellular pathways dependent on Ikbkap/Elp1 (CNS)

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.

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Analysis of peripheral neuron protein expression in the absence of Ikbkap/Elp1

Project description:Familial dysautonomia (FD) results from mutation in IKBKAP/ELP1, a gene encoding the scaffolding protein for the Elongator complex. This highly conserved complex is required for the methoxy-carbonyl-methyl (mcm5) modification of uridines located in the wobble position of tRNA molecules (U34). In FD, the peripheral nervous system is particularly devastated by loss of IKBKAP. Here we investigate protein expression within the dorsal root ganglia (DRG) of a mouse model of FD. In this model, Ikbkap is selectively deleted in the neural crest lineage using a Wnt1-Cre transgene and floxed Ikbkap. DRG were collected and pooled from seven Ikbkap conditional knockout (Wnt1-Cre;IkbkapLoxP/LoxP) and seven control E17.5 mice and analyzed via UHPLC-MS/MS.

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Expression data from P15 mouse testes control and Ikbkap-knockout mice

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Expression data from P15 mouse testes control and Ikbkap-knockout mice

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Control and Ikbkap-knockout MEFs LC-MSMS

Project description:Mouse Ikbkap gene encodes IKAP/Elp1- one of the core subunits of Elongator- and has been implicated in translational regulation. However, a role for IKAP in genome maintenance remains unclear. In this study, we analyze proteins from control and Ikbkap depletion mouse embryonic fibroblasts (MEF) using MS. Using MS-based proteomics, we show that several proteins involved in cancer and DNA damage response were found to be differentially expressed upon Ikbkap depletion.

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Next Generation Sequencing Facilitates Quantitative Analysis of Wild Type (WT), AAG-/-, and ELP1-/- Transcriptomes

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Transcriptome analysis of familial dysautonomia reveals tissue-specific gene expression disruption in the peripheral nervous system

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

Transcriptome analyses of the nervous system of Familial Dysautonomia-model mice identify novel cellular pathways dependent on Ikbkap/Elp1

Project description:Transcriptome analyses of the nervous system of Familial Dysautonomia-model mice identify novel cellular pathways dependent on Ikbkap/Elp1

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