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Axelrod, Felicia B.

doi:10.1007/s102860200014

Cited by 63 publications

(6 citation statements)

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“…Furthermore, we demonstrate here that Ikbkap CKO retinas had decreased complex I activity and ATP levels compared with control retinas, which might explain the poor growth, rhabdomyolysis and reduced muscle tone observed in FD patients ( Axelrod, 2002 ; Riley et al, 1949 ). Intriguingly, a muscle biopsy conducted on an FD patient revealed a severe impairment of mitochondrial complex I, III and IV activity (A.S., personal communication).…”

Section: Discussionmentioning

confidence: 58%

“…A point-mutation in intron 20 results in tissue-specific exon skipping and generates an unstable mRNA, causing a loss-of-function phenotype predominantly in the nervous system ( Cuajungco et al, 2003 ; Dietrich et al, 2012 ; Keren et al, 2010 ). FD patients suffer from congenital and progressive neuropathies, including reduced peripheral afferent sensory function, unstable blood pressure, hypotonia, poor growth and spinal curvature; patients often die in early adulthood owing to sudden unexpected death during sleep ( Axelrod, 2002 ; Palma et al, 2014 , 2017 ; Riley et al, 1949 ). The complete functional repertoire of IKAP/ELP1 remains unresolved, but includes a key role as the scaffolding subunit of the six-subunit elongator complex (ELP1-6) that modifies wobble uridine subunits of tRNA during translation ( Bauer and Hermand, 2012 ; Chen et al, 2009a ; Huang et al, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

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Retina-specific loss of Ikbkap/Elp1 causes mitochondrial dysfunction that leads to selective retinal ganglion cell degeneration in a mouse model of familial dysautonomia

Ueki

Shchepetkina

Lefcort

2018

Disease Models &Amp; Mechanisms

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Familial dysautonomia (FD) is an autosomal recessive disorder marked by developmental and progressive neuropathies. It is caused by an intronic point-mutation in the IKBKAP/ELP1 gene, which encodes the inhibitor of κB kinase complex-associated protein (IKAP, also called ELP1), a component of the elongator complex. Owing to variation in tissue-specific splicing, the mutation primarily affects the nervous system. One of the most debilitating hallmarks of FD that affects patients' quality of life is progressive blindness. To determine the pathophysiological mechanisms that are triggered by the absence of IKAP in the retina, we generated retina-specific Ikbkap conditional knockout (CKO) mice using Pax6-Cre, which abolished Ikbkap expression in all cell types of the retina. Although sensory and autonomic neuropathies in FD are known to be developmental in origin, the loss of IKAP in the retina did not affect its development, demonstrating that IKAP is not required for retinal development. The loss of IKAP caused progressive degeneration of retinal ganglion cells (RGCs) by 1 month of age. Mitochondrial membrane integrity was breached in RGCs, and later in other retinal neurons. In Ikbkap CKO retinas, mitochondria were depolarized, and complex I function and ATP were significantly reduced. Although mitochondrial impairment was detected in all Ikbkap-deficient retinal neurons, RGCs were the only cell type to degenerate; the survival of other retinal neurons was unaffected. This retina-specific FD model is a useful in vivo model for testing potential therapeutics for mitigating blindness in FD. Moreover, our data indicate that RGCs and mitochondria are promising targets.

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Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Retina-specific loss of Ikbkap/Elp1 causes mitochondrial dysfunction that leads to selective retinal ganglion cell degeneration in a mouse model of familial dysautonomia

Ueki

Shchepetkina

Lefcort

2018

Disease Models &Amp; Mechanisms

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“…There is also ataxia and progressive atrophy of the optic nerve that eventually leads to vision loss ( 2 , 4 , 5 ). More than 99% of FD patients are homozygous for the c.2204 + 6T > C intronic splice site mutation in the ELP1 gene ( 6 , 7 ). This gene, located on chromosome 9q31, is 66.60 kb long and has 37 exons ( 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

Exon-specific U1 snRNAs improve ELP1 exon 20 definition and rescue ELP1 protein expression in a familial dysautonomia mouse model

Donadon

Pinotti

Rajkowska

et al. 2018

Human Molecular Genetics

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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.

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“…Elp1 mutations have been linked to an autosomal recessive disorder, FD (Anderson et al, 2001; Slaugenhaupt et al, 2001; Cuajungco et al, 2003). FD is among the most frequent hereditary sensory and autonomic neuropathies (Axelrod and Abularrage, 1982; Axelrod, 2002). The progressive degeneration of the sensory and autonomic nervous system in FD patients results in the following symptoms: cardiovascular dysfunction, pain insensitivity, gastrointestinal dysfunction, scoliosis, vomiting, defective lacrimation, extensive sweating and postural hypotension (Aguayo et al, 1971; Axelrod and Abularrage, 1982).…”

Section: Elongator Defects In Neurological Disordersmentioning

confidence: 99%

The Many Faces of Elongator in Neurodevelopment and Disease

Kojic

Wainwright

2016

Front. Mol. Neurosci.

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Development of the nervous system requires a variety of cellular activities, such as proliferation, migration, axonal outgrowth and guidance and synapse formation during the differentiation of neural precursors into mature neurons. Malfunction of these highly regulated and coordinated events results in various neurological diseases. The Elongator complex is a multi-subunit complex highly conserved in eukaryotes whose function has been implicated in the majority of cellular activities underlying neurodevelopment. These activities include cell motility, actin cytoskeleton organization, exocytosis, polarized secretion, intracellular trafficking and the maintenance of neural function. Several studies have associated mutations in Elongator subunits with the neurological disorders familial dysautonomia (FD), intellectual disability (ID), amyotrophic lateral sclerosis (ALS) and rolandic epilepsy (RE). Here, we review the various cellular activities assigned to this complex and discuss the implications for neural development and disease. Further research in this area has the potential to generate new diagnostic tools, better prevention strategies and more effective treatment options for a wide variety of neurological disorders.

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Cited by 63 publications

References 0 publications

Retina-specific loss of Ikbkap/Elp1 causes mitochondrial dysfunction that leads to selective retinal ganglion cell degeneration in a mouse model of familial dysautonomia

Retina-specific loss of Ikbkap/Elp1 causes mitochondrial dysfunction that leads to selective retinal ganglion cell degeneration in a mouse model of familial dysautonomia

Exon-specific U1 snRNAs improve ELP1 exon 20 definition and rescue ELP1 protein expression in a familial dysautonomia mouse model

The Many Faces of Elongator in Neurodevelopment and Disease

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