Mutation in saposin D domain of sphingolipid activator protein gene causes urinary system defects and cerebellar Purkinje cell degeneration with accumulation of hydroxy fatty acid-containing ceramide in mouse

Matsuda, Junko; Kido, Miki; Tadano-Aritomi, Keiko; Ishizuka, Ineo; Tominaga, Kikuo; Toida, Kazunori; Takeda, Eiji; Suzuki, Kazuyuki; Kuroda, Yasuhiro

doi:10.1093/hmg/ddh281

Cited by 91 publications

(113 citation statements)

References 55 publications

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“…Saposin D stimulates lysosomal ceramide degradation by acid ceramidase and, in vitro, sphingomyelin hydrolysis by acid sphingomyelinase. Saposin D-deficient mice accumulate ceramides in the brain and kidney (23).…”

mentioning

confidence: 99%

Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules

Yuan

Tsang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

102

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CD1d molecules bind lipid antigens in the endocytic pathway, and access to the pathway is important for the development of CD1d-restricted natural killer T (NKT) cells. Saposins, derived from a common precursor, prosaposin, are small, heat-stable lysosomal glycoproteins required for lysosomal degradation of sphingolipids. Expression of prosaposin is required for efficient lipid binding and recognition of human CD1d molecules by NKT cells. Despite high sequence homology among the four saposins, they have different specificities for lipid substrates and different mechanisms of action. To determine the saposins involved in promoting lipid binding to CD1d, we expressed prosaposin deletion mutants lacking individual saposins in prosaposin-negative, CD1d-positive cells. No individual saposin proved to be absolutely essential, but the absence of saposin B resulted in the lowest recognition of α-galactosylceramide by NKT cells. When recombinant exogenous saposins were added to the prosaposin-negative cells, saposin B was the most efficient in restoring CD1d recognition. Saposin B was also the most efficient in mediating α-galactosylceramide binding to recombinant plate-bound CD1d and facilitating NKT cell activation. Saposin B could also mediate lipid binding to soluble CD1d molecules in a T cell-independent assay. The optimal pH for saposin B-mediated lipid binding to CD1d, pH 6, is higher than that of lysosomes, suggesting that saposin B may facilitate lipid binding to CD1d molecules throughout the endocytic pathway.

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mentioning

confidence: 99%

Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules

Yuan

Tsang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

102

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“…The region responsible for this "neuritogenic" effect is a 22 amino acid region within saposin C . There is evidence that saposin D acts as an acid ceramidase inhibitor, whereas mice deficient in saposin D demonstrate renal pathology, imbalance, and loss of cerebellar Purkinje cells (Matsuda et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Progressive Deafness and Altered Cochlear Innervation in Knock-Out Mice Lacking Prosaposin

Akil¹,

Chang²,

Hiel³

et al. 2006

J. Neurosci.

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“…Tissue sections from paraformaldehydefixed brains were processed and stained with anti-calbindin D-28K as described (29). Quantification of Purkinje cells was performed by counting the total number of calbindin-immunoreactive cell bodies in the Purkinje cell layer.…”

Section: Methodsmentioning

confidence: 99%

Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann–Pick C disease

Langmade

Gale

Frolov

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

152

145

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Niemann-Pick type C1 (NPC1) disease is a fatal neurodegenerative disease characterized by neuronal lipid storage and progressive Purkinje cell loss in the cerebellum. We investigated whether therapeutic approaches to bypass the cholesterol trafficking defect in NPC1 disease might delay disease progression in the npc1 ؊/؊ mouse model. We show that the neurosteroid allopregnanolone (ALLO) and T0901317, a synthetic oxysterol ligand, act in concert to delay onset of neurological symptoms and prolong the lifespan of npc1 ؊/؊ mice. ALLO and T0901317 therapy preserved Purkinje cells, suppressed cerebellar expression of microglial-associated genes and inflammatory mediators, and reduced infiltration of activated microglia in the cerebellar tissue. To establish whether the mechanism of neuroprotection in npc1 ؊/؊ mice involves GABAA receptor activation, we compared treatment of natural ALLO and ent-ALLO, a stereoisomer that has identical physical properties of natural ALLO but is not a GABA A receptor agonist. ent-ALLO provided identical functional and survival benefits as natural ALLO in npc1 ؊/؊ mice, strongly supporting a GABAA receptor-independent mechanism for ALLO action. On the other hand, the efficacy of ALLO, ent-ALLO, and T0901317 therapy correlated with the ability of these compounds to activate pregnane X receptor-dependent pathways in vivo. These findings suggest that treatment with pregnane X receptor ligands may be useful clinically in delaying the progressive neurodegeneration in human NPC disease.cholesterol ͉ neurosteroid ͉ allopregnanolone ͉ neurodegeneration N iemann-Pick type C (NPC) disease is an autosomal recessive neurodegenerative disorder characterized by accumulation of cholesterol and other lipids in the viscera and central nervous system and patterned Purkinje cell death in the cerebellum (1). Mutations in the NPC1 gene are responsible for Ϸ95% of human NPC disease. NPC1 loss-of-function mutants exhibit marked impairment of low-density lipoprotein (LDL) cholesterol esterification and mobilization of newly hydrolyzed LDL cholesterol to the plasma membrane (2-4), resulting in lysosomal sequestration of LDL cholesterol, delayed down-regulation of the LDL receptor and de novo cholesterol biosynthesis, and impaired ABCA1-mediated cholesterol efflux (5-7). Despite recent progress in characterizing the biochemical and genetic defects in NPC disease, the mechanisms underlying the neurodegenerative phenotype are not well understood. Moreover, at present there are no effective therapies that delay progression of human NPC disease.Many of the prominent neuropathological features of human NPC disease [e.g., neuronal lipid storage and progressive loss of Purkinje neurons (1)] are recapitulated in the BALB͞c NPC nih (npc1 Ϫ/Ϫ ) mouse, a naturally occurring murine model that harbors a retroposon insertion in the Npc1 gene (8, 9). In NPC1 mice, accumulation of unesterified cholesterol and gangliosides occurs in morphologically normal neurons as early as postnatal day 9 (P9) and precedes neuronal injury and c...

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Mutation in saposin D domain of sphingolipid activator protein gene causes urinary system defects and cerebellar Purkinje cell degeneration with accumulation of hydroxy fatty acid-containing ceramide in mouse

Cited by 91 publications

References 55 publications

Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules

Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules

Progressive Deafness and Altered Cochlear Innervation in Knock-Out Mice Lacking Prosaposin

Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann–Pick C disease

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