title: Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration.
abstract: Sphingolipids typically have an 18-carbon (C18) sphingoid long chain base (LCB) backbone. Although sphingolipids with LCBs of other chain lengths have been identified, the functional significance of these low-abundance sphingolipids is unknown. The LCB chain length is determined by serine palmitoyltransferase (SPT) isoenzymes, which are trimeric proteins composed of two large subunits (SPTLC1 and SPTLC2 or SPTLC3) and a small subunit (SPTssa or SPTssb). Here we report the identification of an Sptssb mutation, Stellar (Stl), which increased the SPT affinity toward the C18 fatty acyl-CoA substrate by twofold and significantly elevated 20-carbon (C20) LCB production in the mutant mouse brain and eye, resulting in surprising neurodegenerative effects including aberrant membrane structures, accumulation of ubiquitinated proteins on membranes, and axon degeneration. Our work demonstrates that SPT small subunits play a major role in controlling SPT activity and substrate affinity, and in specifying sphingolipid LCB chain length in vivo. Moreover, our studies also suggest that excessive C20 LCBs or C20 LCB-containing sphingolipids impair protein homeostasis and neural functions.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609; lihong.zhao@jax.org patsy.nishina@jax.org.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Stefka
authors.initials: S
authors.lastname: Spassieva
authors.affiliation: Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
authors.forename: Kenneth
authors.initials: K
authors.lastname: Gable
authors.affiliation: Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
authors.forename: Sita D
authors.initials: SD
authors.lastname: Gupta
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Lan-Ying
authors.initials: LY
authors.lastname: Shi
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Jieping
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Wanda L
authors.initials: WL
authors.lastname: Hicks
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Mark P
authors.initials: MP
authors.lastname: Krebs
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Juergen
authors.initials: J
authors.lastname: Naggert
authors.affiliation: Stony Brook Cancer Center, Health Science Center, Stony Brook University, Stony Brook, NY 11794.
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.affiliation: Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Dunn
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609; lihong.zhao@jax.org patsy.nishina@jax.org.
authors.forename: Patsy M
authors.initials: PM
authors.lastname: Nishina
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002244:Carbon / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D051102:Serine C-Palmitoyltransferase / Q000737:chemistry* / Q000235:genetics; D054875:Ubiquitination
chemical_list: D002244:Carbon; D051102:Serine C-Palmitoyltransferase
keywords: axon degeneration; long chain base; neurodegeneration; serine palmitoyltransferase; sphingolipid