Phosphatidylserine Ameliorates Neurodegenerative Symptoms and Enhances Axonal Transport in a Mouse Model of Familial Dysautonomia

Shiran Naftelberg,Sivan Yannai,Tal Gradus,Shani Gluska,Keren Ben-Yaakov,Yuvraj Joshi,Gil Ast,Maya Donyo,Chen Farhy,Jonathan Zonszain,Ruth Ashery-Padan,Ziv Abramovitch,Eran Perlson,Gregory S Barsh

doi:10.1371/journal.pgen.1006486

Shiran Naftelberg, Sivan Yannai + Show 12 more

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https://doi.org/10.1371/journal.pgen.1006486

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Journal: PLoS Genetics	Publication Date: Dec 20, 2016
Citations: 32	License type: CC BY 4.0

Affiliation: Tel Aviv University

Abstract

Familial Dysautonomia (FD) is a neurodegenerative disease in which aberrant tissue-specific splicing of IKBKAP exon 20 leads to reduction of IKAP protein levels in neuronal tissues. Here we generated a conditional knockout (CKO) mouse in which exon 20 of IKBKAP is deleted in the nervous system. The CKO FD mice exhibit developmental delays, sensory abnormalities, and less organized dorsal root ganglia (DRGs) with attenuated axons compared to wild-type mice. Furthermore, the CKO FD DRGs show elevated HDAC6 levels, reduced acetylated α-tubulin, unstable microtubules, and impairment of axonal retrograde transport of nerve growth factor (NGF). These abnormalities in DRG properties underlie neuronal degeneration and FD symptoms. Phosphatidylserine treatment decreased HDAC6 levels and thus increased acetylation of α-tubulin. Further PS treatment resulted in recovery of axonal outgrowth and enhanced retrograde axonal transport by decreasing histone deacetylase 6 (HDAC6) levels and thus increasing acetylation of α-tubulin levels. Thus, we have identified the molecular pathway that leads to neurodegeneration in FD and have demonstrated that phosphatidylserine treatment has the potential to slow progression of neurodegeneration.

Highlights

Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that occurs almost exclusively in the Ashkenazi Jewish population with a remarkably high carrier frequency ranging from 1 in 18 to 1 in 32 [1]
We create a novel FD mouse model, in which exon 20 of IKBKAP was deleted in the nervous system, to study the role of IκB kinase complex-associated protein (IKAP) in the neurodegeneration process
Reduction of IKAP levels resulted in elevated histone deacetylase 6 (HDAC6) levels and reduced acetylated α-tubulin levels

Summary

Introduction

Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that occurs almost exclusively in the Ashkenazi Jewish population with a remarkably high carrier frequency ranging from 1 in 18 (in those of Polish descent) to 1 in 32 [1]. Previous work discovered that the underlying genetic cause of FD is a point mutation in the IKBKAP gene, which encodes the IκB kinase complex-associated protein (IKAP) [7,8]. A transition from T to C at position 6 of the 5’ splice site of IKBKAP intron 20 [8] alters the splicing pattern of the IKBKAP gene in a tissue-specific manner: There is a shift from constitutive inclusion of exon 20 to alternative splicing in all tissues, and in the nerve tissues this exon is predominantly skipped [9]. No truncated protein has been detected in tissues of FD patients [8,10,11]; there is a considerable reduction in full-length IKAP protein expression in the nervous systems of FD patients [8,11]

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