Last update 01 Nov 2024

ELP1

Last update 01 Nov 2024

Basic Info

Synonyms

DYS, elongator acetyltransferase complex subunit 1, Elongator complex protein 1

+ [8]

Introduction

Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine) (PubMed:29332244). The elongator complex catalyzes the formation of carboxymethyluridine in the wobble base at position 34 in tRNAs (PubMed:29332244). Regulates the migration and branching of projection neurons in the developing cerebral cortex, through a process depending on alpha-tubulin acetylation (By similarity). ELP1 binds to tRNA, mediating interaction of the elongator complex with tRNA (By similarity). May act as a scaffold protein that assembles active IKK-MAP3K14 complexes (IKKA, IKKB and MAP3K14/NIK) (PubMed:9751059).

Drugs associated with ELP1

PTC-0405403

Target

ELP1 x splicing factor

Mechanism

ELP1 modulators [+1]

Active Org.

PTC Therapeutics, Inc. [+2]

Originator Org.

The General Hospital Corp.

Active Indication

Dysautonomia, Familial

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ELP1

100 Translational Medicine associated with ELP1

0 Patents (Medical) associated with ELP1

372

Literatures (Medical) associated with ELP1

11 Sep 2024·The Journal of Neuroscience

ELP1, the Gene Mutated in Familial Dysautonomia, Is Required for Normal Enteric Nervous System Development and Maintenance and for Gut Epithelium Homeostasis

Article

Author: Kaufmann, Horacio ; Henningsen, Katelyn ; Chaverra, Marta ; George, Lynn ; Miller, Alessa ; Walk, Seth ; Scheel, Alpha ; Cheney, Alexandra M ; Schultz, Anastasia ; Kominsky, Douglas ; Lefcort, Frances ; Kennedy, William R ; Copié, Valérie ; Walk, Heather

Familial dysautonomia (FD) is a rare sensory and autonomic neuropathy that results from a mutation in theELP1gene. Virtually all patients report gastrointestinal (GI) dysfunction and we have recently shown that FD patients have a dysbiotic gut microbiome and altered metabolome. These findings were recapitulated in an FD mouse model and moreover, the FD mice had reduced intestinal motility, as did patients. To understand the cellular basis for impaired GI function in FD, the enteric nervous system (ENS; both female and male mice) from FD mouse models was analyzed during embryonic development and adulthood. We show here that not only isElp1required for the normal formation of the ENS, but it is also required in adulthood for the regulation of both neuronal and non-neuronal cells and for target innervation in both the mucosa and in intestinal smooth muscle. In particular, CGRP innervation was significantly reduced as was the number of dopaminergic neurons. Examination of an FD patient's gastric biopsy also revealed reduced and disoriented axons in the mucosa. Finally, using an FD mouse model in whichElp1was deleted exclusively from neurons, we found significant changes to the colon epithelium including reduced E-cadherin expression, perturbed mucus layer organization, and infiltration of bacteria into the mucosa. The fact that deletion ofElp1exclusively in neurons is sufficient to alter the intestinal epithelium and perturb the intestinal epithelial barrier highlights a critical role for neurons in regulating GI epithelium homeostasis.

01 Sep 2024·Neurobiology of Disease

Loss of Elp1 in cerebellar granule cell progenitors models ataxia phenotype of Familial Dysautonomia

Article

Author: Joshi, Piyush ; Ahmad, Shiekh Tanveer ; Radoš, Magdalena ; Northcott, Paul A ; Li, Yiran ; Kutscher, Lena M ; Spänig, Lisa ; Bianchini, Luca ; Schouw, Mackenna E ; Patrizi, Annarita ; Lin, Hong ; Lukasch, Chiara ; Garcia-Lopez, Jesus ; Sepp, Mari ; Roiuk, Mykola ; da Silva, Patricia Benites Goncalves ; Arnskötter, Frederik ; Sieber, Laura ; Zuckermann, Marc

Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have also been described. Although ELP1 expression remains high in the normal developing and adult cerebellum, its role in cerebellar development is unknown. To explore the role of Elp1 in the cerebellum, we knocked out Elp1 in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition. We found that GCP-specific conditional knockout of Elp1 (Elp1^cKO) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent as early as 7 days after birth, when Elp1^cKO animals also had fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of Elp1 was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of ELP1 in the developing cerebellum, and suggests that loss of Elp1 in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.

10 Jul 2024·Histology and histopathology

Brain endothelial cell activation and dysfunction associate with and contribute to the development of enlarged perivascular spaces and cerebral small vessel disease.

Review

Author: Hayden, Melvin Ray

Multiple injurious stimuli to the brain's endothelium results in brain endothelial cell activation and dysfunction (BECact/dys) with upregulation of inflammatory signaling cascades and a decrease in bioavailable nitric oxide respectively. These injurious stimuli initiate a brain injury and a response to injury wound healing genetically programed cascade of events, which result in cellular remodeling of the neurovascular unit and blood-brain barrier with increased inflammation and permeability. These remodeling changes also include the perivascular spaces that become dilated to form enlarged perivascular spaces (EPVS) that may be identified noninvasively by magnetic resonance imaging. These EPVS are associated with and considered to be a biomarker for cerebral small vessel disease (SVD) and a dysfunctional glymphatic system with impaired removal of neurotoxic waste, which ultimately results in neurodegeneration with impaired cognition and dementia. The penultimate section discusses the understudied role of venous cerebral circulation in relation to EPVS, SVD, and the vascular contribution to cognitive impairment (VCID). The focus of this review will be primarily on BECact/dys that associates with and contributes to the development of EPVS, SVD, and impaired glymphatic system efflux. Importantly, BECact/dys may be a key piece of the puzzle to unlock this complicated story of EPVS and SVD. Multiple transmission electron micrographs and illustrations will be utilized to depict anatomical ultrastructure and allow for the discussion of multiple functional molecular cascades.

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ELP1

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