A Hydrophilic Peptide Comprising 18 Amino Acid Residues of the Prosaposin Sequence Has Neurotrophic Activity In Vitro and In Vivo

Kotani, Yasunori; Matsuda, Seiji; Wen, Tong-Chun; Sakanaka, Masahiro; Tanaka, Junya; Maeda, Nobuji; Kondoh, Keiji; Ueno, Shu‐ichi; Sano, Akira

doi:10.1046/j.1471-4159.1996.66052197.x

Cited by 94 publications

(58 citation statements)

References 15 publications

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“…Saposin C contains a neurotrophic peptide (54)(55)(56) that is present in mammalian but not in chicken prosaposin (47) or in J3-crystallin (present study), suggesting a later evolutionary development. This active peptide, called prosaptide, acts as a Schwann-cell survival factor via a phosphorylation signaltransduction pathway associated with myelin formation (57)(58)(59).…”

Section: Discussionmentioning

confidence: 48%

J3-crystallin of the jellyfish lens: Similarity to saposins

Piatigorsky

Norman

Dishaw

et al. 2001

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

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J3-crystallin, one of the three major eye-lens proteins of the cubomedusan jellyfish (Tripedalia cystophora), shows similarity to vertebrate saposins, which are multifunctional proteins that bridge lysosomal hydrolases to lipids and activate enzyme activity. Sequence alignment of deduced J3-crystallin indicates two saposinlike motifs arranged in tandem, each containing six cysteines characteristic of this protein family. The J3-crystallin cDNA encodes a putative precursor analogous to vertebrate prosaposins. The J3-crystallin gene has seven exons, with exons 2-4 encoding the protein. Exon 3 encodes a circularly permutated saposin motif, called a swaposin, found in plant aspartic proteases. J3-crystallin RNA was found in the cubomedusan lens, statocyst, in bands radiating from the pigmented region of the ocellus, in the tentacle tip by in situ hybridization, and in the embryo and larva by reverse transcription-PCR. Our data suggest a crystallin role for the multifunctional saposin protein family in the jellyfish lens. This finding extends the gene sharing evolutionary strategy for lens crystallins to the cnidarians and indicates that the putative primordial saposin͞swaposin J3-crystallin reflects both the chaperone and enzyme connections of the vertebrate crystallins.C omplex eyes with cellular lenses are scattered throughout the animal phyla from cubomedusan jellyfish to humans. The optical properties of the transparent lens depend on a diverse group of water-soluble, multifunctional proteins called crystallins, many of which are related or identical to stress proteins or metabolic enzymes (1, 2). The ␣-crystallins are small heat-shock protein͞molecular chaperones (3-5), and the ␤͞␥-crystallins (6) are related to microbial stress-protective proteins (7); the ␣-and the ␤͞␥-crystallins are present ubiquitously in vertebrate lenses. By contrast, the enzymecrystallins are expressed selectively in different species. Crystallins are critical for the optical properties of the lens and are essentially defined by their abundance (collectively 80 -90% of the water-soluble protein) in the lens. Most, if not all, of the crystallins also are expressed at lower amounts outside of the lens where they have nonoptical roles. This dual function of crystallins, which depends on their tissue location and quantitative levels, has been called gene sharing (8,9).Recruitment of enzymes as lens crystallins also has occurred in invertebrates (10). This recruitment was first shown for the glutathione S-transferase-related S-crystallins (11, 12) and subsequently for the aldehyde dehydrogenase-related ⍀-crystallin (13, 14) of cephalopods. More recently, aldehyde dehydrogenase͞⍀-crystallin was shown to be the only crystallin in the scallop eye lens (15). Except for one minor S-crystallin (16), the multiple S-crystallins (13, 17, 18) and ⍀-crystallin (14, 15, 19) seem enzymatically inactive.Much less is known about lens crystallins of other invertebrates. Drosocrystallin is a secreted protein forming the transparent sheath of ommatidia in t...

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Section: Discussionmentioning

confidence: 48%

J3-crystallin of the jellyfish lens: Similarity to saposins

Piatigorsky

Norman

Dishaw

et al. 2001

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

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“…Prosaptide is a peptide fragment that mimics the trophic and protective actions of full-length prosaposin (23,24,26,28,32,35,36,38,53,54), but it is widely presumed that full-length prosaposin is the endogenous ligand for any receptor that can be activated by prosaptide. Thus, we purified full-length prosaposin using a slightly modified version of a previously described protocol (58) and assessed whether full-length prosaposin could activate GPR37 and GPR37L1.…”

Section: Resultsmentioning

confidence: 99%

GPR37 and GPR37L1 are receptors for the neuroprotective and glioprotective factors prosaptide and prosaposin

Meyer

Giddens

Schaefer

et al. 2013

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

181

237

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GPR37 (also known as Pael-R) and GPR37L1 are orphan G protein-coupled receptors that are almost exclusively expressed in the nervous system. We screened these receptors for potential activation by various orphan neuropeptides, and these screens yielded a single positive hit: prosaptide, which promoted the endocytosis of GPR37 and GPR37L1, bound to both receptors and activated signaling in a GPR37- and GPR37L1-dependent manner. Prosaptide stimulation of cells transfected with GPR37 or GPR37L1 induced the phosphorylation of ERK in a pertussis toxin-sensitive manner, stimulated 35 S-GTPγS binding, and promoted the inhibition of forskolin-stimulated cAMP production. Because prosaptide is the active fragment of the secreted neuroprotective and glioprotective factor prosaposin (also known as sulfated glycoprotein-1), we purified full-length prosaposin and found that it also stimulated GPR37 and GPR37L1 signaling. Moreover, both prosaptide and prosaposin were found to protect primary astrocytes against oxidative stress, with these protective effects being attenuated by siRNA-mediated knockdown of endogenous astrocytic GPR37 or GPR37L1. These data reveal that GPR37 and GPR37L1 are receptors for the neuroprotective and glioprotective factors prosaptide and prosaposin.

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“…It was demonstrated that prosaposin possesses a strong protective action against ischemic damage to hippocampal neurons when infused intracerebroventrically before ischemia (Sano et al, 1994), suggesting that prosaposin may be neurotrophic in action. It is further suggested that the in vitro and in vivo trophic actions of prosaposin on hippocampal and cortical neurons are related to a linear 18-mer prosaposin-derived peptide (18MP: LSELIINNATEELLIKGL) comprising the hydrophilic sequence of the rat saposin C domain (Kotani et al, 1996). However, the role of 18MP in molecular mechanisms of ischemia-induced neuronal degeneration remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of a Prosaposin-Derived, 18-Mer Peptide on Slowly Progressive Neuronal Degeneration after Brief Ischemia

Morita

Wen

Tanaka

et al. 2001

J Cereb Blood Flow Metab

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Summary:Slowly progressive degeneration of the hippocampal CA1 neurons was induced by 3-minute transient global ischemia in gerbils. Sustained degeneration of hippocampal CA1 neurons was evident 1 month after ischemia. To investigate the effects of an 18-mer peptide comprising the hydrophilic sequence of the rat saposin C domain (18MP) on this sustained neuronal degeneration, an intracerebroventricular 18MP infusion was initiated 3 days after ischemia. Histopathologic and behavior evaluations were conducted 1 week and 1 month after induction of ischemia. When compared with the vehicle infusion, 18MP treatment significantly increased the response latency time in a passive avoidance task. Increased neuronal density was also evident, as was the number of intact synapses in the hippocampal CA1 region at 1 week and 1 month after ischemia. 18MP treatment also significantly decreased the number of TUNEL-positive CA1 neurons 1 week after ischemia. Subsequent in vitro experiments using cultured neurons demonstrated that the 18MP at optimal extracellular concentrations of 1 to 100 fg/mL prevented nitric oxideinduced neuronal damage as expected and significantly upregulated the expressions of bcl-x L mRNA and its translated protein. These results suggest that the gerbil model of 3-minute ischemia is useful in studying the pathogenesis of slowly progressive neuronal degeneration after stroke and in evaluating effects of novel therapeutic agents. It is likely that the 18MP at low extracellular concentrations prevents neuronal apoptosis possibly through up-regulation of the mitochondrial antiapoptotic factor Bcl-x L .

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A Hydrophilic Peptide Comprising 18 Amino Acid Residues of the Prosaposin Sequence Has Neurotrophic Activity In Vitro and In Vivo

Cited by 94 publications

References 15 publications

J3-crystallin of the jellyfish lens: Similarity to saposins

J3-crystallin of the jellyfish lens: Similarity to saposins

GPR37 and GPR37L1 are receptors for the neuroprotective and glioprotective factors prosaptide and prosaposin

Protective Effect of a Prosaposin-Derived, 18-Mer Peptide on Slowly Progressive Neuronal Degeneration after Brief Ischemia

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