Phosphatidylserine Reverses Neurodegeneration in Mouse Model of Familial Dysautonomia

A genetically engineered mouse model system was used to study the role of the IKAP protein in the neurodegeneration process that underlies the genetic disease Familial dysautonomia and to show that treatment with phosphatidylserine could alleviate symptoms of the disease.

Familial dysautonomia (FD) is found almost exclusively in Ashkenazi Jews and is inherited in an autosomal recessive fashion with a carrier frequency of about one in 30. FD is a disorder of the autonomic nervous system, which does not affect intelligence but rather affects the development and survival of sensory, sympathetic, and some parasympathetic neurons in the autonomic and sensory nervous. Individuals with FD have frequent vomiting crises, pneumonia, problems with speech and movement, difficulty swallowing, inappropriate perception of heat, pain, and taste, as well as unstable blood pressure and gastrointestinal dysfunction.


At the molecular level FD is characterized by aberrant tissue-specific splicing of the IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein) gene at exon 20, which leads to reduction of IKAP protein levels in neuronal tissues.

To study the molecular mechanism behind FD, investigators at Tel Aviv University (Israel) generated a conditional knockout (CKO) mouse line in which exon 20 of IKBKAP was deleted in the nervous system. They reported in the December 20, 2016, online edition of the journal PLOS Genetics that the CKO FD mice exhibited developmental delays, sensory abnormalities, and less organized dorsal root ganglia (DRGs) with attenuated axons compared to wild-type mice. DRGs from the CKO mice were grossly reduced in size relative to DRGs in control mice and overall the neuronal network formation was compromised. Furthermore, DRGs from the CKO mice showed elevated levels of the enzyme HDAC6 (Histone deacetylase 6), reduced acetylated alpha-tubulin, unstable microtubules, and impairment of axonal retrograde transport of nerve growth factor (NGF).

The investigators went on to show that phosphatidylserine treatment decreased HDAC6 levels and thus increased acetylation of alpha-tubulin. Further phosphatidylserine treatment resulted in recovery of axonal outgrowth and enhanced retrograde axonal transport by decreasing HDAC6 levels and thus increasing acetylation of alpha-tubulin levels. These results suggested that phosphatidylserine acted as an HDAC6 inhibitor to improve neurological function.

"We identified the molecular pathway that leads to neurodegeneration in FD and demonstrated that phosphatidylserine has the potential to slow progression of neurodegeneration," said senior author Dr. Gil Ast, professor of human genetics at Tel Aviv University.

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