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

Lefler, Sharon; Cohen, Malkiel A.; Kantor, Gal; Cheishvili, David; Even, Aviel; Birger, Anastasya; Turetsky, Tikva; Gil, Yaniv; Even-Ram, Sharona; Aizenman, Einat; Bashir, Nibal; Maayan, Channa; Razin, Aharon; Reubinoff, Benjamin; Weil, Miguel

doi:10.1371/journal.pone.0138807

Cited by 25 publications

(31 citation statements)

References 61 publications

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“…Moreover, IKAP was also shown to interact directly with the motor protein dynein, suggesting that IKAP may also be involved in intracellular transport (Abashidze et al , 2014). These initial findings were further corroborated by transcriptome analyses in neuronal differentiated FD-derived embryonic stem cells as well as in FD embryonic brains (Lefler et al , 2015). In particular, these analyses revealed that in FD-derived neurons and embryonic brains synaptic vesicular and neuronal transport genes are directly or indirectly affected by IKAP depletion (Lefler et al , 2015).…”

Section: Ikap Cellular Functions: Implications For Pns Deficitsmentioning

confidence: 60%

“…These initial findings were further corroborated by transcriptome analyses in neuronal differentiated FD-derived embryonic stem cells as well as in FD embryonic brains (Lefler et al , 2015). In particular, these analyses revealed that in FD-derived neurons and embryonic brains synaptic vesicular and neuronal transport genes are directly or indirectly affected by IKAP depletion (Lefler et al , 2015). Significantly, among the five types of HSANs, FD (HSAN III), HSAN IV (caused by mutations in NGF receptor), and HSAN V (caused by mutations in NGF) share several similarities.…”

Section: Ikap Cellular Functions: Implications For Pns Deficitsmentioning

confidence: 60%

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Familial Dysautonomia: Mechanisms and Models

Dietrich

Dragatsis

2016

Genet. Mol. Biol.

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Hereditary Sensory and Autonomic Neuropathies (HSANs) compose a heterogeneous group of genetic disorders characterized by sensory and autonomic dysfunctions. Familial Dysautonomia (FD), also known as HSAN III, is an autosomal recessive disorder that affects 1/3,600 live births in the Ashkenazi Jewish population. The major features of the disease are already present at birth and are attributed to abnormal development and progressive degeneration of the sensory and autonomic nervous systems. Despite clinical interventions, the disease is inevitably fatal. FD is caused by a point mutation in intron 20 of the IKBKAP gene that results in severe reduction in expression of IKAP, its encoded protein. In vitro and in vivo studies have shown that IKAP is involved in multiple intracellular processes, and suggest that failed target innervation and/or impaired neurotrophic retrograde transport are the primary causes of neuronal cell death in FD. However, FD is far more complex, and appears to affect several other organs and systems in addition to the peripheral nervous system. With the recent generation of mouse models that recapitulate the molecular and pathological features of the disease, it is now possible to further investigate the mechanisms underlying different aspects of the disorder, and to test novel therapeutic strategies.

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Section: Ikap Cellular Functions: Implications For Pns Deficitsmentioning

confidence: 60%

Section: Ikap Cellular Functions: Implications For Pns Deficitsmentioning

confidence: 60%

Familial Dysautonomia: Mechanisms and Models

Dietrich

Dragatsis

2016

Genet. Mol. Biol.

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“…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%

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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“…One outstanding question is the physiological mechanisms mediating the erratic, elevated levels of dopamine in FD patient plasma that trigger the vomiting crises during “autonomic storms” [70]. Studies in yeast have shown that IKAP negatively regulates exocytosis [20], and evidence has been provided for IKAP localization to synaptic vesicles [24] raising the testable question of whether aberrant regulation of synaptic transmission may explain some of the autonomic dysfunction in FD. Another question that can be addressed with these animal and cellular models are the underlying metabolic problems experienced by FD patients and recapitulated in mice: patients have a significantly decreased body mass index (BMI), and multiple studies on FD mouse models report weight reductions of 60–70% in mutant mice with an absence of white adipose tissue.…”

Section: Resultsmentioning

confidence: 99%

“…Due to their pluripotent nature, stem cells can be differentiated into neuronal cells, thereby providing a powerful system for modeling human diseases in vitro . FD human embryonic stem cell (hESC) or induced pluripotent stem cell (iPSC)-derived peripheral nervous system progenitor cells (neural crest) and neurons have been generated and can serve as a potential tool to investigate the molecular mechanisms mediating the demise of neurons in FD [24, 61–64]. In addition, the feasibility of large-scale small molecule screening using FD-iPSCs [62] has facilitated the discovery of potential therapeutic compounds that can increase splicing of the mutated IKBKAP mRNA in FD-patient iPSC-derived neural crest cells, and increase expression of genes that regulate the differentiation of sympathetic neurons such as ASCL1 and SCG10 .…”

Section: Stem Cell 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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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

Cited by 25 publications

References 61 publications

Familial Dysautonomia: Mechanisms and Models

Familial Dysautonomia: Mechanisms and Models

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

Animal and cellular models of familial dysautonomia

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