Transcriptome analyses of the nervous system of Familial Dysautonomia-model mice identify novel cellular pathways dependent on Ikbkap/Elp1
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA318069MSV000081568PRJNA318068
ORGANISM(S): Mus musculus
PROVIDER: GSE80165 | GEO | 2018/04/26
REPOSITORIES: GEO
Similar Datasets
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:Transcriptome analyses of the nervous system of Familial Dysautonomia-model mice identify novel cellular pathways dependent on Ikbkap/Elp1
| PRJNA318069 | ENA
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:The successful completion of the Human Genome Project led to the discovery of the molecular basis of thousands of genetic disorders. The identification of the mutations that cause familial dysautonomia (FD), an autosomal recessive disorder that impacts sensory and autonomic neurons, was aided by the release of the human DNA sequence. The identification and characterization of the genetic cause of FD have changed the natural history of this disease. Genetic testing programs, which were established shortly after the disease-causing mutations were identified, have almost completely eliminated the birth of children with this disorder. Characterization of the principal disease-causing mutation has led to the development of therapeutic modalities that ameliorate its effect, while the development of mouse models that recapitulate the impact of the mutation has allowed for the in-depth characterization of its impact on neuronal development and survival. The intense research focus on this disorder, while clearly benefiting the FD patient population, also serves as a model for the positive impact focused research efforts can have on the future of other genetic diseases. Here, we present the research advances and scientific breakthroughs that have changed and will continue to change the natural history of this centuries-old genetic disease.
| S-EPMC5735983 | biostudies-literature
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 sensory and autonomic neuropathy caused by mutations in elongator complex protein 1 (ELP1). FD patients have small trigeminal nerves and impaired facial pain and temperature perception. These signals are relayed by nociceptive neurons in the trigeminal ganglion, a structure that is composed of both neural crest- and placode-derived cells. Mice lacking Elp1 in neural crest derivatives ('Elp1 CKO') are born with small trigeminal ganglia, suggesting Elp1 is important for trigeminal ganglion development, yet the function of Elp1 in this context is unknown. We demonstrate that Elp1, expressed in both neural crest- and placode-derived neurons, is not required for initial trigeminal ganglion formation. However, Elp1 CKO trigeminal neurons exhibit abnormal axon outgrowth and deficient target innervation. Developing nociceptors expressing the receptor TrkA undergo early apoptosis in Elp1 CKO, while TrkB- and TrkC-expressing neurons are spared, indicating Elp1 supports the target innervation and survival of trigeminal nociceptors. Furthermore, we demonstrate that specific TrkA deficits in the Elp1 CKO trigeminal ganglion reflect the neural crest lineage of most TrkA neurons versus the placodal lineage of most TrkB and TrkC neurons. Altogether, these findings explain defects in cranial gangliogenesis that may lead to loss of facial pain and temperature sensation in FD.
| S-EPMC9273214 | biostudies-literature
Project description:Familial dysautonomia (FD) is a rare genetic disease with no treatment, caused by an intronic point mutation (c.2204+6T>C) that negatively affects the definition of exon 20 in the elongator complex protein 1 gene (ELP1 also known as IKBKAP). This substitution modifies the 5' splice site and, in combination with regulatory splicing factors, induces different levels of exon 20 skipping, in various tissues. Here, we evaluated the therapeutic potential of a novel class of U1 snRNA molecules, exon-specific U1s (ExSpeU1s), in correcting ELP1 exon 20 recognition. Lentivirus-mediated expression of ELP1-ExSpeU1 in FD fibroblasts improved ELP1 splicing and protein levels. We next focused on a transgenic mouse model that recapitulates the same tissue-specific mis-splicing seen in FD patients. Intraperitoneal delivery of ELP1-ExSpeU1s-adeno-associated virus particles successfully increased the production of full-length human ELP1 transcript and protein. This splice-switching class of molecules is the first to specifically correct the ELP1 exon 20 splicing defect. Our data provide proof of principle of ExSpeU1s-adeno-associated virus particles as a novel therapeutic strategy for FD.
| S-EPMC6030917 | biostudies-literature
Project description:Since Riley and Day first described the clinical phenotype of patients with familial dysautonomia (FD) over 60 years ago, the field has made considerable progress clinically, scientifically, and translationally in treating and understanding the etiology of FD. FD is classified as a hereditary sensory and autonomic neuropathy (HSAN type III) and is both a developmental and a progressive neurodegenerative condition that results from an autosomal recessive mutation in the gene IKBKAP, also known as ELP1. FD primarily impacts the peripheral nervous system but also manifests in central nervous system disruption, especially in the retina and optic nerve. While the disease is rare, the rapid progress being made in elucidating the molecular and cellular mechanisms mediating the demise of neurons in FD should provide insight into degenerative pathways common to many neurological disorders. Interestingly, the protein encoded by IKBKAP/ELP1, IKAP or ELP1, is a key scaffolding subunit of the six-subunit Elongator complex, and variants in other Elongator genes are associated with amyotrophic lateral sclerosis (ALS), intellectual disability, and Rolandic epilepsy. Here we review the recent model systems that are revealing the molecular and cellular pathophysiological mechanisms mediating FD. These powerful model systems can now be used to test targeted therapeutics for mitigating neuronal loss in FD and potentially other disorders.
| S-EPMC5722227 | biostudies-literature
Project description:Familial dysautonomia (FD) is characterized by severe and progressive sympathetic and sensory neuron loss caused by a highly conserved germline point mutation of the human ELP1/IKBKAP gene. Elp1 is a subunit of the hetero-hexameric transcriptional elongator complex, but how it functions in disease-vulnerable neurons is unknown. Conditional knockout mice were generated to characterize the role of Elp1 in migration, differentiation and survival of migratory neural crest (NC) progenitors that give rise to sympathetic and sensory neurons. Loss of Elp1 in NC progenitors did not impair their migration, proliferation or survival, but there was a significant impact on post-migratory sensory and sympathetic neuron survival and target tissue innervation. Ablation of Elp1 in post-migratory sympathetic neurons caused highly abnormal target tissue innervation that was correlated with abnormal neurite outgrowth/branching and abnormal cellular distribution of soluble tyrosinated ?-tubulin in Elp1-deficient primary sympathetic and sensory neurons. These results indicate that neuron loss and physiologic impairment in FD is not a consequence of abnormal neuron progenitor migration, differentiation or survival. Rather, loss of Elp1 leads to neuron death as a consequence of failed target tissue innervation associated with impairments in cytoskeletal regulation.
| S-EPMC4050699 | 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