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Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration.
Zhao, Lihong; Spassieva, Stefka; Gable, Kenneth; Gupta, Sita D; Shi, Lan-Ying; Wang, Jieping; Bielawski, Jacek; Hicks, Wanda L; Krebs, Mark P; Naggert, Juergen; Hannun, Yusuf A; Dunn, Teresa M; Nishina, Patsy M.
Afiliación
  • Zhao L; The Jackson Laboratory, Bar Harbor, ME 04609; lihong.zhao@jax.org patsy.nishina@jax.org.
  • Spassieva S; Department of Medicine, Medical University of South Carolina, Charleston, SC 29425;
  • Gable K; Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
  • Gupta SD; Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
  • Shi LY; The Jackson Laboratory, Bar Harbor, ME 04609;
  • Wang J; The Jackson Laboratory, Bar Harbor, ME 04609;
  • Bielawski J; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425;
  • Hicks WL; The Jackson Laboratory, Bar Harbor, ME 04609;
  • Krebs MP; The Jackson Laboratory, Bar Harbor, ME 04609;
  • Naggert J; The Jackson Laboratory, Bar Harbor, ME 04609;
  • Hannun YA; Stony Brook Cancer Center, Health Science Center, Stony Brook University, Stony Brook, NY 11794.
  • Dunn TM; Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
  • Nishina PM; The Jackson Laboratory, Bar Harbor, ME 04609; lihong.zhao@jax.org patsy.nishina@jax.org.
Proc Natl Acad Sci U S A ; 112(42): 12962-7, 2015 Oct 20.
Article en En | MEDLINE | ID: mdl-26438849
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Carbono / Enfermedades Neurodegenerativas / Serina C-Palmitoiltransferasa / Mutación Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2015 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Carbono / Enfermedades Neurodegenerativas / Serina C-Palmitoiltransferasa / Mutación Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2015 Tipo del documento: Article