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

PLoS Genet. 2016 Dec 20;12(12):e1006486. doi: 10.1371/journal.pgen.1006486. eCollection 2016 Dec.


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.

MeSH terms

  • Alternative Splicing / genetics
  • Animals
  • Axonal Transport / drug effects*
  • Axonal Transport / genetics
  • Axons / drug effects
  • Disease Models, Animal
  • Dysautonomia, Familial / drug therapy
  • Dysautonomia, Familial / genetics*
  • Dysautonomia, Familial / pathology
  • Exons / genetics
  • Ganglia, Spinal / growth & development
  • Ganglia, Spinal / pathology
  • Histone Deacetylase 6
  • Histone Deacetylases / biosynthesis
  • Histone Deacetylases / genetics*
  • Humans
  • Mice
  • Mice, Knockout
  • Nerve Degeneration / drug therapy
  • Nerve Degeneration / genetics
  • Nerve Degeneration / pathology
  • Nerve Growth Factor / genetics
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphatidylserines / administration & dosage*
  • Phosphatidylserines / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Tubulin / genetics*


  • Phosphatidylserines
  • Tubulin
  • Nerve Growth Factor
  • Hdac6 protein, mouse
  • Histone Deacetylase 6
  • Histone Deacetylases

Grant support

Funding for this work was provided by grants from the Israel Science Foundation (ISF) [142/13, 1439/14], Teva Pharmaceutical Industries Ltd as part of the Israeli National Network of Excellence in Neuroscience (NNE) [1234944, DKFZ-MOST (German Cancer Research Center and Ministry of Science, Technology and Space, 3-13113), and by Dysautonomia Foundation. EP was supported by grants from the Israel Science Foundation (ISF) [561/11]; and the European Research Council (ERC) [309377]. SN was supported by grants from Teva Pharmaceutical Industries Ltd. under the Israeli National Network of Excellence in Neuroscience. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.