title: 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.
authors.affiliation: Department of Human Molecular Genetics and Biochemestry. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shiran
authors.initials: S
authors.lastname: Naftelberg
authors.affiliation: Department of Human Molecular Genetics and Biochemestry. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Abramovitch
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Gluska
authors.affiliation: Department of Human Molecular Genetics and Biochemestry. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Sivan
authors.initials: S
authors.lastname: Yannai
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yuvraj
authors.initials: Y
authors.lastname: Joshi
authors.affiliation: Department of Human Molecular Genetics and Biochemestry. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Donyo
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Keren
authors.initials: K
authors.lastname: Ben-Yaakov
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Gradus
authors.affiliation: Department of Human Molecular Genetics and Biochemestry. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Zonszain
authors.affiliation: Department of Human Molecular Genetics and Biochemestry. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Farhy
authors.affiliation: Department of Human Molecular Genetics and Biochemestry. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Ashery-Padan
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Perlson
authors.affiliation: Department of Human Molecular Genetics and Biochemestry. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Gil
authors.initials: G
authors.lastname: Ast
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects* / Q000235:genetics; D001369:Axons / Q000187:drug effects; D004195:Disease Models, Animal; D004402:Dysautonomia, Familial / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005091:Exons / Q000235:genetics; D005727:Ganglia, Spinal / Q000254:growth & development / Q000473:pathology; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D020932:Nerve Growth Factor / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010718:Phosphatidylserines / Q000008:administration & dosage* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014404:Tubulin / Q000235:genetics*
chemical_list: D010718:Phosphatidylserines; D014404:Tubulin; D020932:Nerve Growth Factor; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases