title: Phosphatidylserine increases IKBKAP levels in a humanized knock-in IKBKAP mouse model.
abstract: Familial dysautonomia (FD) is a severe neurodegenerative genetic disorder restricted to the Ashkenazi Jewish population. The most common mutation in FD patients is a T-to-C transition at position 6 of intron 20 of the IKBKAP gene. This mutation causes aberrant skipping of exon 20 in a tissue-specific manner, leading to reduction of the IκB kinase complex-associated protein (IKAP) protein in the nervous system. We established a homozygous humanized mouse strain carrying human exon 20 and its two flanking introns; the 3' intron has the transition observed in the IKBKAP gene of FD patients. Although our FD humanized mouse does not display FD symptoms, the unique, tissue-specific splicing pattern of the IKBKAP in these mice allowed us to evaluate the effect of therapies on gene expression and exon 20 splicing. The FD mice were supplemented with phosphatidylserine (PS), a safe food supplement that increases mRNA and protein levels of IKBKAP in cell lines generated from FD patients. Here we demonstrated that PS treatment increases IKBAKP mRNA and IKAP protein levels in various tissues of FD mice without affecting exon 20 inclusion levels. We also observed that genes associated with transcription regulation and developmental processes were up-regulated in the cerebrum of PS-treated mice. Thus, PS holds promise for the treatment of FD.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry.
authors.forename: Ron
authors.initials: R
authors.lastname: Bochner
authors.forename: Yael
authors.initials: Y
authors.lastname: Ziv
authors.forename: David
authors.initials: D
authors.lastname: Zeevi
authors.forename: Maya
authors.initials: M
authors.lastname: Donyo
authors.forename: Lital
authors.initials: L
authors.lastname: Abraham
authors.forename: Ruth
authors.initials: R
authors.lastname: Ashery-Padan
authors.forename: Gil
authors.initials: G
authors.lastname: Ast
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004402:Dysautonomia, Familial / Q000235:genetics / Q000378:metabolism*; D005091:Exons; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007438:Introns; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010718:Phosphatidylserines / Q000378:metabolism*; D035602:Transcriptional Elongation Factors
chemical_list: D002352:Carrier Proteins; C114720:Elp1 protein, human; C491968:Ikbkap protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D010718:Phosphatidylserines; D035602:Transcriptional Elongation Factors