Phosphatidylserine Increases IKBKAP Levels in Familial Dysautonomia Cells

Keren, Hadas; Donyo, Maya; Zeevi, David; Maayan, Channa; Pupko, Tal; Ast, Gil

doi:10.1371/journal.pone.0015884

Cited by 38 publications

(48 citation statements)

References 55 publications

(79 reference statements)

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“…This suggests that the compensatory response to reduced slo-1 levels is to diminish the levels of other genes involved in cell depolarization. Many human diseases are the result of intronic point mutations (Watanabe et al 2000;Lamba et al 2002;Keren et al 2010); identifying ectopic genetic responses provides potential therapeutic routes to alleviate the effects of such diseases.…”

Section: Discussionmentioning

confidence: 99%

Cell Excitability Necessary for Male Mating Behavior inCaenorhabditis elegansIs Coordinated by Interactions Between Big Current and Ether-A-Go-Go Family K+ Channels

LeBoeuf

García

2012

Genetics

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Variations in K + channel composition allow for differences in cell excitability and, at an organismal level, provide flexibility to behavioral regulation. When the function of a K + channel is disrupted, the remaining K + channels might incompletely compensate, manifesting as abnormal organismal behavior. In this study, we explored how different K + channels interact to regulate the neuromuscular circuitry used by Caenorhabditis elegans males to protract their copulatory spicules from their tail and insert them into the hermaphrodite's vulva during mating. We determined that the big current K + channel (BK)/SLO-1 genetically interacts with ether-a-gogo (EAG)/EGL-2 and EAG-related gene/UNC-103 K + channels to control spicule protraction. Through rescue experiments, we show that specific slo-1 isoforms affect spicule protraction. Gene expression studies show that slo-1 and egl-2 expression can be upregulated in a calcium/calmodulin-dependent protein kinase II-dependent manner to compensate for the loss of unc-103 and conversely, unc-103 can partially compensate for the loss of SLO-1 function. In conclusion, an interaction between BK and EAG family K + channels produces the muscle excitability levels that regulate the timing of spicule protraction and the success of male mating behavior.

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Section: Discussionmentioning

confidence: 99%

Cell Excitability Necessary for Male Mating Behavior inCaenorhabditis elegansIs Coordinated by Interactions Between Big Current and Ether-A-Go-Go Family K+ Channels

LeBoeuf

García

2012

Genetics

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“…Several attempts have been made to search for therapeutic chemical compounds that promote exon 20 inclusion in patients with FD by quantifying RT-PCR analysis in patient cells or reporter-transfected cells (11)(12)(13)(14)(15)(16). Even with the most potent splicing modifier, the previously identified plant cytokinin kinetin, however, the effect is not sufficiently strong or specific to promote exon 20 inclusion in IKBKAP (15,16).…”

Section: Significancementioning

confidence: 99%

Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia

Yoshida

Kataoka

Miyauchi

et al. 2015

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

103

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Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by missplicing of exon 20, resulting from an intronic mutation in the inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) gene encoding IKK complex-associated protein (IKAP)/elongator protein 1 (ELP1). A newly established splicing reporter assay allowed us to visualize pathogenic splicing in cells and to screen small chemicals for the ability to correct the aberrant splicing of IKBKAP. Using this splicing reporter, we screened our chemical libraries and identified a compound, rectifier of aberrant splicing (RECTAS), that rectifies the aberrant IKBKAP splicing in cells from patients with FD. Here, we found that the levels of modified uridine at the wobble position in cytoplasmic tRNAs are reduced in cells from patients with FD and that treatment with RECTAS increases the expression of IKAP and recovers the tRNA modifications. These findings suggest that the missplicing of IKBKAP results in reduced tRNA modifications in patients with FD and that RECTAS is a promising therapeutic drug candidate for FD. IKAP is currently known as elongator protein 1 (ELP1), an integral component of the human Elongator complex, which was originally identified in Saccharomyces cerevisiae and shown to be well conserved among species (1). Although multiple functions of IKAP/ELP1 in JNK signaling, neuronal development during embryogenesis, exocytosis, and actin cytoskeleton regulation have been reported (reviewed in refs. 2, 3), yeast genetic analyses have shown that the Elongator complex is also required for the formation of the C5-substituent of 5-carbamoylmethyl (ncm 5 ), 5-methoxycarbonylmethyl (mcm 5 ), and its derivatives at the wobble uridine in tRNAs recognizing purine-ending codons (4, 5). Most recently, it was demonstrated that conditional IKAP/Elp1 KO in mouse testes results in male infertility by disrupting meiotic progression, along with the reduction of modified nucleosides [5-methoxycarbonylmethyl uridine (mcm 5 U), 5-carbamoylmethyl uridine (ncm 5 U), and 5-methoxycarbonylmethyl-2-thiouridine (mcm 5 s 2 U)] of total tRNAs in the testes (6). These modifications are highly likely to play critical roles in the maintenance of translational fidelity, suggesting that the defects in these modifications lead to the mistranslation of various proteins.Familial dysautonomia (FD; Riley-Day syndrome), an autosomal recessive neurodegenerative disease, is characterized by impaired development and progressive degeneration of the sensory and autonomic nerves. Patients who have FD exhibit various symptoms, including cardiovascular instability, recurrent pneumonia, vomiting/dysautonomic crisis, gastrointestinal dysfunction, decreased sensitivity to pain and temperature, and defective lacrimation. FD is a very common disorder in the Ashkenazi Jewish population, with a carrier frequency of 1 in 27. More than 99% of patients who have FD harbor a homozygous mutation in intron 20 (IVS20 + 6T > C: FD mutation)...

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“…Phosphatidylserine, a phospholipidic component of cell membranes, has been shown to raise IKAP (ELP-1) levels in cell lines and animal models of FD. 96, 97 Initial studies of phosphatidylserine in a small number of FD patients have demonstrated an increase in IKAP (ELP-1) levels and have shown that it is safe and well tolerated. 98 Long-term trials are underway to determine whether raising IKAP (ELP-1) levels can rescue or delay the progressive worsening of neurological features like optic atrophy and gait ataxia.…”

Section: Splicing Modification Therapymentioning

confidence: 99%

Current treatments in familial dysautonomia

Palma

Kaufmann

Fuente-Mora

et al. 2014

Expert Opinion on Pharmacotherapy

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Introduction Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy (type III). The disease is caused by a point mutation in the IKBKAP gene that affects the splicing of the elongator-1 protein (also known as IKAP). Patients have dramatic blood pressure instability due to baroreflex failure, chronic kidney disease, and impaired swallowing leading to recurrent aspiration pneumonia, which results in chronic lung disease. Diminished pain and temperature perception results in neuropathic joints and thermal injuries. Impaired proprioception leads to gait ataxia. Optic neuropathy and corneal opacities lead to progressive visual loss. Areas covered This article reviews current therapeutic strategies for the symptomatic treatment of FD, as well as the potential of new gene modifying agents. Expert opinion Therapeutic focus on FD is centered on reducing the catecholamine surges caused by baroreflex failure. Managing neurogenic dysphagia with effective protection of the airway passages and prompt treatment of aspiration pneumonias is necessary to prevent respiratory failure. Sedative medications should be used cautiously due to risk of respiratory depression. Non-invasive ventilation during sleep effectively manages apneas and prevents hypercapnia. Clinical trials of compounds that increase levels of IKAP (ELP-1) are underway and will determine whether they can reverse or slow disease progression.

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Phosphatidylserine Increases IKBKAP Levels in Familial Dysautonomia Cells

Cited by 38 publications

References 55 publications

Cell Excitability Necessary for Male Mating Behavior inCaenorhabditis elegansIs Coordinated by Interactions Between Big Current and Ether-A-Go-Go Family K+ Channels

Cell Excitability Necessary for Male Mating Behavior inCaenorhabditis elegansIs Coordinated by Interactions Between Big Current and Ether-A-Go-Go Family K+ Channels

Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia

Current treatments in familial dysautonomia

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