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Abstract
Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that results from abnormal development and progressive degeneration of the sensory and autonomic nervous system. The mutation observed in almost all FD patients is a point mutation at position 6 of intron 20 of the IKBKAP gene; this gene encodes the IκB kinase complex-associated protein (IKAP). The mutation results in a tissue-specific splicing defect: Exon 20 is skipped, leading to reduced IKAP protein expression. Here we show that phosphatidylserine (PS), an FDA-approved food supplement, increased IKAP mRNA levels in cells derived from FD patients. Long-term treatment with PS led to a significant increase in IKAP protein levels in these cells. A conjugate of PS and an omega-3 fatty acid also increased IKAP mRNA levels. Furthermore, PS treatment released FD cells from cell cycle arrest and up-regulated a significant number of genes involved in cell cycle regulation. Our results suggest that PS has potential for use as a therapeutic agent for FD. Understanding its mechanism of action may reveal the mechanism underlying the FD disease.
Highlights
Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy that occurs almost exclusively in the Ashkenazi Jewish population with a carrier frequency between 1 in 27 to 1 in 32 [1,2]
A cell line derived from a parent of an FD patient, and heterozygous for the FD mutation, and four matched cell lines derived from healthy individuals were used as controls
FD is caused by a mutation in the IKBKAP gene that leads to aberrant splicing
Summary
Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy that occurs almost exclusively in the Ashkenazi Jewish population with a carrier frequency between 1 in 27 to 1 in 32 [1,2]. Ashkenazi Jews of Polish descent have a higher carrier frequency of 1 in 18 [3]. FD results from abnormal development and progressive degeneration of the sensory and autonomic nervous system. Patients are severely affected with a variety of symptoms in most body systems. Among these symptoms are gastrointestinal and cardiovascular dysfunction, vomiting crises, abnormal sensitivity to pain and temperature, and recurrent pneumonia. Despite recent advances in patient management, about 50% of patients die before the age of 40 [4,5,6]
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