Involvement of IKAP in Peripheral Target Innervation and in Specific JNK and NGF Signaling in Developing PNS Neurons

Abashidze, Anastasia; Gold, Veronica; Anavi, Yaron; Greenspan, Hayit; Weil, Miguel

doi:10.1371/journal.pone.0113428

Cited by 40 publications

(76 citation statements)

References 37 publications

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“…It has been postulated that neurons die in FD because of an inability to innervate correctly their targets from which they receive essential survival stimuli in the form of neurotrophins (36,37). We show here that incubation in NGF is insufficient to rescue the small-diameter TrkA + , Ikbkap −/− neurons.…”

Section: Bgp-15 Normalizes Impaired Actin Dynamics In Ikbkapmentioning

confidence: 64%

“…Specifically, Elongator has been demonstrated to be required for normal neuronal branching (36,37,41,(48)(49)(50)(51), organization of actin networks (38), and acetylation of α-tubulin (40, 50, 52). Microtubules also have been shown to be altered in growth cones from peripheral neurons lacking IKAP/ELP1 in chick (36). BGP-15 did not induce any significant improvements in Ikbkap −/− microtubule networks (i.e., it did not promote the growth of the Ikbkap −/− axons).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, restoration of actin network function could improve neuronal survival, because actin dynamics mediate vesicle transport and are required specifically for the TrkA/NGF endosomal retrograde survival signaling in DRG neurons (53) that is necessary to prevent the default apoptotic response (46). Previous studies have suggested a role of IKAP/ELP1 in neuronal transport (36,54), and recent work has revealed that the speed of NGF retrograde transport is reduced in neurons lacking Ikbkap (40). Additionally, Rac-1, which interacts with actin to regulate growth cone dynamics (55), has been demonstrated in mammalian cells to be a target of BGP-15 treatment (31,32) and potentially could contribute to the positive effects of BGP-15 on the actin cytoskeleton, because actin has been shown to activate signaling cascades that lead to apoptosis (56).…”

Section: Discussionmentioning

confidence: 99%

“…However, the failure to extend or maintain axons to mediate normal transport during target innervation could also ultimately cause neuronal death. In support of this thesis, IKAP/ELP1 has been shown to be necessary for normal cytoskeletal dynamics (36,38,39) and for the retrograde transport of NGF (40), whereas ELP3, the acetyl-transferase subunit of the Elongator complex, has been proposed to regulate actin dynamics (13,41). For a better understanding of why Ikbkap −/− neurons die, we investigated their behavior in vitro, examining their overall morphology, axon outgrowth, and growth cone dynamics.…”

Section: Bgp-15 Normalizes Impaired Actin Dynamics In Ikbkapmentioning

confidence: 95%

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BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Ohlen

Russell

Brownstein

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Hereditary sensory and autonomic neuropathy type III, or familial dysautonomia [FD; Online Mendelian Inheritance in Man (OMIM) 223900], affects the development and long-term viability of neurons in the peripheral nervous system (PNS) and retina. FD is caused by a point mutation in the gene IKBKAP/ELP1 that results in a tissue-specific reduction of the IKAP/ELP1 protein, a subunit of the Elongator complex. Hallmarks of the disease include vasomotor and cardiovascular instability and diminished pain and temperature sensation caused by reductions in sensory and autonomic neurons. It has been suggested but not demonstrated that mitochondrial function may be abnormal in FD. We previously generated an Ikbkap/Elp1 conditional-knockout mouse model that recapitulates the selective death of sensory (dorsal root ganglia) and autonomic neurons observed in FD. We now show that in these mice neuronal mitochondria have abnormal membrane potentials, produce elevated levels of reactive oxygen species, are fragmented, and do not aggregate normally at axonal branch points. The small hydroxylamine compound BGP-15 improved mitochondrial function, protecting neurons from dying in vitro and in vivo, and promoted cardiac innervation in vivo. Given that impairment of mitochondrial function is a common pathological component of neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's, Parkinson's, and Huntington's diseases, our findings identify a therapeutic approach that may have efficacy in multiple degenerative conditions.T he autonomic nervous system is essential for homeostasis, and its disruption in familial dysautonomia (FD) can have fatal consequences resulting from cardiovascular instability, respiratory dysfunction, and/or sudden death during sleep (1-3). In addition to developmental decreases in the number of sensory and autonomic neurons, FD patients undergo a progressive loss of peripheral neurons and retinal ganglion cells. The latter loss may ultimately lead to blindness (4, 5). More than 98% of FD cases result from a single base substitution (IVS20+6T > C) in the IKBKAP/ELP1 gene (3, 6). This mutation is carried by 1 in 27 to 1 in 32 Ashkenazi Jews (3, 6). The protein encoded by the IKBKAP/ELP1 gene, IKAP/ELP1, is a scaffolding protein for the six-subunit Elongator complex (ELP1-ELP6), which modifies tRNAs during translation (7). Why reduction in the IKAP/ ELP1 protein results in neuronal death is unknown, and we have sought to elucidate the cellular and molecular mechanisms that cause progressive neurodegeneration in FD to help identify treatments that improve neuronal function and viability.Accumulating evidence indicates that cells from FD patients and from mouse models with deletions in the Elongator subunits Ikbkap/Elp1 or Elp3 experience intracellular stress (4,5,(8)(9)(10) resulting from the direct and/or indirect consequences of impaired translation (7, 11). The C terminus of IKAP/ELP1 has been shown to bind c-Jun N-terminal kinase (JNK) and to regulate JNK cytosolic stress signaling (12)....

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Section: Bgp-15 Normalizes Impaired Actin Dynamics In Ikbkapmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Bgp-15 Normalizes Impaired Actin Dynamics In Ikbkapmentioning

confidence: 95%

See 2 more Smart Citations

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Ohlen

Russell

Brownstein

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Studies in C.elegans , zebrafish, chick and Drosophila all show a requirement for IKAP and/or the Elongator complex in normal axonal morphology, with reductions in Ikbkap/Elp1 causing abnormal branching [28, 38, 39], reduced vesicle movement along microtubules, disrupted target innervation [38, 40], and compromised c-Jun N-terminal Kinase (JNK) and Nerve Growth Factor (NGF) signaling [38]. In addition, mutants lacking Ikbkap/Elp1 and/or the Elongator complex had abnormal synaptic function [40], larval development [40–42] and learning impairment [41].…”

Section: Non-mammalian Models Of Familial Dysautonomiamentioning

confidence: 99%

Animal and cellular models of familial dysautonomia

et al. 2017

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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.

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The crucial role of model systems in understanding the complexity of cell signaling in human neurocristopathies

Cerrizuela

Vega-Lopez

Méndez-Maldonado

et al. 2021

WIREs Mechanisms of Disease

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Animal models are useful to study the molecular, cellular, and morphogenetic mechanisms underlying normal and pathological development. Cell‐based study models have emerged as an alternative approach to study many aspects of human embryonic development and disease. The neural crest (NC) is a transient, multipotent, and migratory embryonic cell population that generates a diverse group of cell types that arises during vertebrate development. The abnormal formation or development of the NC results in neurocristopathies (NCPs), which are characterized by a broad spectrum of functional and morphological alterations. The impaired molecular mechanisms that give rise to these multiphenotypic diseases are not entirely clear yet. This fact, added to the high incidence of these disorders in the newborn population, has led to the development of systematic approaches for their understanding. In this article, we have systematically reviewed the ways in which experimentation with different animal and cell model systems has improved our knowledge of NCPs, and how these advances might contribute to the development of better diagnostic and therapeutic tools for the treatment of these pathologies. This article is categorized under: Congenital Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Stem Cells and Development Congenital Diseases > Molecular and Cellular Physiology Neurological Diseases > Genetics/Genomics/Epigenetics

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Involvement of IKAP in Peripheral Target Innervation and in Specific JNK and NGF Signaling in Developing PNS Neurons

Cited by 40 publications

References 37 publications

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Animal and cellular models of familial dysautonomia

The crucial role of model systems in understanding the complexity of cell signaling in human neurocristopathies

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