Protection by Prosaposin Against Ischemia-Induced Learning Disability and Neuronal Loss

Sano, Akira; Matsuda, Seiji; Wen, Tong-Chun; Kotani, Yasunori; Kondoh, Keiji; Ueno, Shu Ichi; Kakimoto, Yasuo; Yoshimura, Hidetoshi; Sakanaka, Masahiro

doi:10.1006/bbrc.1994.2558

Cited by 95 publications

(54 citation statements)

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“…One unit of EPO approximately corresponds to 10 ng of EPO protein. EPO at a dose of 0.5 (n ϭ 8), 2.5 (n ϭ 8), 5 (n ϭ 11), or 25 (n ϭ 8) unit͞day was infused for 7 days into the left lateral ventricle of each normothermic gerbil in which 3-min forebrain ischemia had been induced as described (18)(19)(20)(21)(22)(23); control animals (one group with 3-min forebrain ischemia and one group of shamoperated animals) received vehicle infusion (n ϭ 11 in each group). To investigate the neuroprotective effect of endogenous brain EPO on ischemic CA1 neurons, sEPOR (24) at a dose of 5, 10, 25, or 50 g͞day was infused for 7 days into the left lateral ventricles of normothermic gerbils in which 2.5-min forebrain ischemia had been induced (n ϭ 6-8 in each group).…”

Section: Methodsmentioning

confidence: 99%

In vivo evidence that erythropoietin protects neurons from ischemic damage

Sakanaka

Wen²,

Matsuda³

et al. 1998

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

881

657

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Erythropoietin (EPO) produced by the kidney and the liver (in fetuses) stimulates erythropoiesis. In the central nervous system, neurons express EPO receptor (EPOR) and astrocytes produce EPO. EPO has been shown to protect primary cultured neurons from N-methyl-D-aspartate (NMDA) receptor-mediated glutamate toxicity. Here we report in vivo evidence that EPO protects neurons against ischemia-induced cell death. Infusion of EPO into the lateral ventricles of gerbils prevented ischemia-induced learning disability and rescued hippocampal CA1 neurons from lethal ischemic damage. The neuroprotective action of exogenous EPO was also confirmed by counting synapses in the hippocampal CA1 region. Infusion of soluble EPOR (an extracellular domain capable of binding with the ligand) into animals given a mild ischemic treatment that did not produce neuronal damage, caused neuronal degeneration and impaired learning ability, whereas infusion of the heatdenatured soluble EPOR was not detrimental, demonstrating that the endogenous brain EPO is crucial for neuronal survival. The presence of EPO in neuron cultures did not repress a NMDA receptor-mediated increase in intracellular Ca 2؉ , but rescued the neurons from NO-induced death. Taken together EPO may exert its neuroprotective effect by reducing the NO-mediated formation of free radicals or antagonizing their toxicity.Mammals respond to oxygen deficiency in many different ways (1). One strategy for survival of the individual cells under hypoxic conditions is the induction of glycolytic enzymes, facilitating ATP production by glycolysis rather than mitochondrial oxidative phosphorylation. In response to the systemic oxygen deficiency due to anemia or decreasedenvironmental oxygen concentration, erythropoietin (EPO) production is stimulated. EPO is a glycoprotein that stimulates differentiation and proliferation of erythroid precursor cells, and hypoxic induction of EPO production increases red blood cells, leading to better oxygen supply to tissues (2, 3). The action of EPO is mediated by binding to the specific receptor that belongs to a new family of cytokine receptors that have no tyrosine kinase domain (4). EPO regulating erythropoiesis is mainly produced by the kidney in adults and by the liver at fetal stages (2, 3).Stimulation of red blood cell formation was thought to be the sole physiological function of EPO, but a different function in the central nervous system has been proposed (5-7). Neuronal cell lines such as PC12 and SN6 express EPO receptor (EPOR), and binding of EPO to PC12 cells increases the intracellular concentration of monoamines (8). Immunochemical staining with anti-EPOR antibody showed that EPOR is expressed in murine hippocampal and cerebral cortical areas, and also in primary cultured hippocampal and cortical neurons (6, 9). With the use of radioiodinated EPO, specific EPO binding sites were found in some defined areas of the murine brain including the hippocampus and cerebral cortex (10). Because the blood-brain barrier prevents neurons fr...

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Section: Methodsmentioning

confidence: 99%

In vivo evidence that erythropoietin protects neurons from ischemic damage

Sakanaka

Wen²,

Matsuda³

et al. 1998

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

881

657

View full text Add to dashboard Cite

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“…We have described (3) several synthetic peptides derived from this region that are as biologically active as prosaposin; we named these peptides ''prosaptides.'' Prosaposin and prosaptides are active on a variety of neuronal cells including hippocampal neurons (5,6), spinal cord ␣-motor neurons (7), sensory neurons of the dorsal root ganglion (7), cerebellar granule cell neurons (3), and neuroblastoma cells (2)(3)(4)8). In each of these cells, prosaposin or prosaptides stimulate neurite outgrowth in nanomolar concentrations and prevent cell death.…”

mentioning

confidence: 99%

Cell death prevention, mitogen-activated protein kinase stimulation, and increased sulfatide concentrations in Schwann cells and oligodendrocytes by prosaposin and prosaptides

Hiraiwa

Taylor

Campana

et al. 1997

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

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Prosaposin, the precursor of saposins A, B, C, and D, was recently identified as a neurotrophic factor. Herein prosaposin was found to increase sulfatide concentrations in primary and transformed Schwann cells (iSC) and oligodendrocytes (differentiated CG4 cells). Of the four mature saposins, only saposin C was found to increase sulfatide concentrations in these cell types. A similar result was obtained by using peptides (

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“…as a ganglioside-binding protein (7). Moreover, SAP precursor was also identified as a neurotrophic factor in vivo (8,9). However, detailed studies on the mechanisms of endocytosis and intracellular processing of SAP precursor are still missing.…”

mentioning

confidence: 99%

Biosynthesis, Processing, and Targeting of Sphingolipid Activator Protein (SAP)Precursor in Cultured Human Fibroblasts

Vielhaber

Hurwitz

Sandhoff

1996

Journal of Biological Chemistry

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Sphingolipid activator proteins (SAPs) are essential cofactors for the lysosomal degradation of glycosphingolipids with short oligosaccharide chains by acidic exohydrolases. SAP-A, -B, -C, and -D derive from proteolysis of a 73-kDa glycoprotein, the SAP precursor. In the present publication, we studied the intracellular transport and the endocytosis of SAP precursor in human skin fibroblasts. Our data indicate that SAP precursor bears phosphate residues on noncomplex carbohydrate chains linked to the SAP-C and the SAP-D domain and sulfate residues on complex carbohydrate chains located within the SAP-A, -C, and possibly the SAP-D domain. Treatment of fibroblasts with either bafilomycin A 1 or 3-methyladenine indicates that proteolytic cleavage of SAP precursor begins as early as in the late endosomes. To determine whether targeting of SAP precursor depends on mannose 6-phosphate residues, we analyzed the processing of SAP precursor in I-cell disease fibroblasts. In these cells nearly normal amounts of newly synthesized SAP-C were found, although secretion of SAP precursor was enhanced 2-3-fold. Moreover, SAP-C could be localized to lysosomal structures by indirect immunofluorescence in normal and in I-cell disease fibroblasts. Mannose 6-phosphate was not found to interfere significantly with endocytosis of SAP precursor. Normal fibroblasts internalized SAP precursor secreted from I-cells nearly as efficiently as the protein secreted from normal cells. To our surprise, deglycosylated SAP precursor was taken up by mannose 6-phosphate receptor double knock out mouse fibroblasts more efficiently than the glycosylated protein. We propose that intracellular targeting of SAP precursor to lysosomes is only partially dependent on mannose 6-phosphate residues, whereas its endocytosis occurs in a carbohydrate-independent manner.

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Protection by Prosaposin Against Ischemia-Induced Learning Disability and Neuronal Loss

Cited by 95 publications

References 0 publications

In vivo evidence that erythropoietin protects neurons from ischemic damage

In vivo evidence that erythropoietin protects neurons from ischemic damage

Cell death prevention, mitogen-activated protein kinase stimulation, and increased sulfatide concentrations in Schwann cells and oligodendrocytes by prosaposin and prosaptides

Biosynthesis, Processing, and Targeting of Sphingolipid Activator Protein (SAP)Precursor in Cultured Human Fibroblasts

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