scholarly journals Loss of Elp1 perturbs histone H2A.Z and the Notch signaling pathway

Biology Open ◽  
2021 ◽  
Vol 10 (9) ◽  
Author(s):  
BreAnna Cameron ◽  
Elin Lehrmann ◽  
Tien Chih ◽  
Joseph Walters ◽  
Richard Buksch ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Translational Regulation ◽  
Trichostatin A ◽  
Notch Signaling Pathway ◽  
Familial Dysautonomia ◽  
Autism Spectrum ◽  
Cellular Processes ◽  
Deacetylase Inhibitor ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
Lateral Sclerosis

ABSTRACT Elongator dysfunction is increasingly recognized as a contributor to multiple neurodevelopmental and neurodegenerative disorders including familial dysautonomia, intellectual disability, amyotrophic lateral sclerosis, and autism spectrum disorder. Although numerous cellular processes are perturbed in the context of Elongator loss, converging evidence from multiple studies has resolved Elongator's primary function in the cell to the modification of tRNA wobble uridines and the translational regulation of codon-biased genes. Here we characterize H2a.z, encoding the variant H2a histone H2A.Z, as an indirect Elongator target. We further show that canonical Notch signaling, a pathway directed by H2A.Z, is perturbed as a consequence of Elp1 loss. Finally, we demonstrate that hyperacetylation of H2A.Z and other histones via exposure to the histone deacetylase inhibitor Trichostatin A during neurogenesis corrects the expression of Notch3 and rescues the development of sensory neurons in embryos lacking the Elp1 Elongator subunit.

scholarly journals Combinatorial Treatment Increases IKAP Levels in Human Cells Generated from Familial Dysautonomia Patients

2019 ◽  
Author(s):  
Sivan Yannai ◽  
Jonathan Zonszain ◽  
Maya Donyo ◽  
Gil Ast
Keyword(s):  
Trichostatin A ◽  
Combined Treatment ◽  
Food Supplement ◽  
Familial Dysautonomia ◽  
Sigma 1 Receptor ◽  
Therapeutic Value ◽  
Deacetylase Inhibitor ◽  
Sigma 1 ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
In Cells

AbstractFamilial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that results from a point mutation at the 5’ splice site of intron 20 in the IKBKAP gene. This mutation decreases production of the IKAP protein, and treatments that increase the level of the full-length IKBKAP transcript are likely to be of therapeutic value. We previously found that phosphatidylserine (PS), an FDA-approved food supplement, elevates IKAP levels in cells generated from FD patients. Here we demonstrate that combined treatment of cells generated from FD patients with PS and kinetin or PS and the histone deacetylase inhibitor trichostatin A (TSA) resulted in an additive elevation of IKAP compared to each drug alone. This indicates that the compounds influence different pathways. We also found that pridopidine enhances production of IKAP in cells generated from FD patients. Pridopidine has an additive effect on IKAP levels when used in combination with kinetin or TSA, but not with PS; suggesting that PS and pridopidine influence IKBKAP levels through the same mechanism. Indeed, we demonstrate that the effect of PS and pridopidine is through sigma-1 receptor-mediated activation of the BDNF signaling pathway. A combination treatment with any of these drugs with different mechanisms has potential to benefit FD patients.

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