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

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.

Author Summary

We create a novel FD mouse model, in which exon 20 of IKBKAP was deleted in the nervous system, to study the role of IKAP in the neurodegeneration process. The lack of IKBKAP exon 20 impaired retrograde nerve growth factor (NGF) transport and axonal outgrowth. Reduction of IKAP levels resulted in elevated HDAC6 levels and thus reduced acetylated α-tubulin levels. Phosphatidylserine down-regulated HDAC6 levels, furthermore phosphatidylserine treatment facilitated axonal transport and stabilized microtubules. In brief: Naftelberg et al. identify the molecular pathway leading to neurodegeneration using a mouse model of familial dysautonomia and suggest that phosphatidylserine acts as an HDAC6 inhibitor to improve neurologic function.