Disease relevance of Psap

• The reversibility and regression of histological and biochemical findings in a mouse model of Gaucher disease (4L/PS-NA) was evaluated using a liver-enriched activator protein promoter control of a tetracycline-controlled transcriptional activation-responsive human acid beta-glucosidase (hGCase) transgenic system [1].
• It is well established, however, that the lysosomes of I-cell disease (ICD) patients have near normal levels of several lysosomal proteins, including prosaposin and GM2AP [2].
• Prosaposin knock-out (PS-/-) mice expressing N or CBC transgenes, even at low levels, had delayed onset of neurologic signs and neuropathology, and significant lengthening of life span (from 1.7- to 7-fold) with age dependent partial correction of GlcCer and LacCer accumulation in the brain [3].
• An animal model was recently developed by creating a null allele in embryonic stem cells through gene targeting in order to investigate the phenotypic diversity of prosaposin mutations, the involvement of this protein in lysosomal storage diseases, and to develop potential therapeutic approaches [4].
• A similar interaction also occurred in the breast cancer cell culture medium between the secreted prosaposin and procath-D [5].

High impact information on Psap

• Cell death prevention, mitogen-activated protein kinase stimulation, and increased sulfatide concentrations in Schwann cells and oligodendrocytes by prosaposin and prosaptides [6].
• These findings suggest that prosaposin and prosaptides bind to a receptor that initiates signal transduction to promote myelin lipid synthesis and prolong cell survival in both Schwann cells and oligodendrocytes [6].
• Prosaposin may function as a myelinotrophic factor in vivo during development and repair of myelinated nerves explaining the deficiency of myelin observed in prosaposin-deficient mice and humans [6].
• Dose-response curves demonstrated that nanomolar concentrations of prosaposin and saposin C stimulated neurite outgrowth and increased ChAT activity [7].
• These results indicate that prosaposin and saposin C are neurotrophic factors which initiate signal transduction by binding to a high-affinity receptor that induces protein phosphorylation [7].

Chemical compound and disease context of Psap

• We conclude that in breast cancer cells, even though procath-D interacts intracellularly and extracellarly with prosaposin, it is endocytosed independent of prosaposin by a receptor different from the M6P receptors and the LRP [5].
• CONCLUSION: We postulate that as a mitogenic, survival, and anti-apoptotic factor for prostate cancer cells, saposin C or prosaposin may contribute to prostate carcinogenesis at its early androgen-dependent or metastatic AI state [8].

Biological context of Psap

• Genetic mapping of the mouse prosaposin gene (Psap) to mouse chromosome 10 [9].
• Gross brain and neuronal organizations were indistinguishable in PS-/- mice with or without the various transgenes, albeit the phenotype appeared later in the mice with transgenes [3].
• Prosaposin (pSAP) is a large precursor protein that is proteolytically cleaved to form four distinct sphingolipid activator proteins, which stimulate enzymatic hydrolysis of sphingolipids, including glucosylceramide [10].
• Gaucher disease mouse models: point mutations at the acid beta-glucosidase locus combined with low-level prosaposin expression lead to disease variants [11].
• Alternative splicing in the prosaposin gene is conserved from fish to humans, tissue specific, and regulated in the brain during development and nerve regeneration-degeneration processes [12].

Anatomical context of Psap

• Interestingly, dominant-negative GGAs, unable to bind clathrin to shuttle from the Golgi, prevented the trafficking of prosaposin and GM2AP to lysosomes [2].
• Prosaposin (SGP-1) and GM2 activator protein (GM2AP) are soluble sphingolipid activator proteins (SAPs) that are targeted to the lysosomal compartment of Sertoli cells to aid hydrolases in the breakdown of glycosphingolipids [2].
• Using a TM4 Sertoli cell line, we tested the hypothesis that prosaposin and GM2AP are targeted to the lysosomal compartment via the sortilin receptor, which has been recently shown to have a GGA binding motif [2].
• Concordant decreases (>50%) of GCase protein and in vitro activity were detected in extracts of cultured fibroblasts and hepatocytes from PS-/- mice and human prosaposin-deficient fibroblasts [13].
• Prosaposin was initially identified in Sertoli cells, found in large amounts in the lysosomal compartment and implicated in the degradation of residual bodies released by the spermatids during spermiation [14].

Associations of Psap with chemical compounds

• The visceral tissue storage cells and glucosylceramide (GC) accumulation in hGCase/4L/PS-NA were decreased from that in 4L/PS-NA mice [1].
• The hGCase/4L/PS-NA had exclusive liver expression of hGCase controlled by doxycycline (DOX) [1].
• Prosaposin is the precursor of four glycoprotein activators (saposins) for lysosomal hydrolases [3].
• A mutation in the saposin A domain of the sphingolipid activator protein (prosaposin) gene results in a late-onset, chronic form of globoid cell leukodystrophy in the mouse [15].
• No changes were detected in prosaposin secretion or in accumulation and metabolism of gangliosides, sulfatides, neutral glycosphingolipids, neutral phospholipids, other neutral lipids, and ceramide [12].

Physical interactions of Psap

• A dominant negative construct of sortilin lacking the GGA binding domain retained prosaposin and GM2AP in the Golgi [2].

Regulatory relationships of Psap

• In prostatic epithelium, targeted disruption of the prosaposin gene appears to inactivate the mitogen-activated protein kinase pathway and to interfere with differentiation of secretory cells [4].

Other interactions of Psap

• Thus, prosaposin and GM2AP can traffic to lysosomes in a MPR independent manner [2].
• Interestingly, the targeting of prosaposin to the lysosomes is independent of the M6P-R [14].
• In vivo roles of RORalpha and Sp4 in the regulation of murine prosaposin gene [16].
• The Golgi apparatus appears to accomplish the molecular sorting of the 65-kDa prosaposin by decoding a signal from its amino acid backbone [17].
• This approach demonstrated that prosaposin mRNAs of brain, heart, and muscle contain the nine base pairs of exon 8, whereas the transcripts from testis, lung, pancreas, spleen, and kidney do not contain this exon 8 [18].

Analytical, diagnostic and therapeutic context of Psap

• To characterize the temporal and spatial expression of the prosaposin locus, prenatal and postnatal mouse tissues were screened by in situ hybridization with a mouse antisense riboprobe for prosaposin [19].
• Sequence analysis revealed that the mouse SGP-1 gene consists of 15 exons ranging from nine base pairs to 298 base pairs and 14 introns, which ranged from 89 base pairs to >8 kb in length [18].
• Thus our investigation dealt with the molecular cloning of the mouse SGP-1 gene [18].
• Expression of the prosaposin gene, implicated in human genetic diseases, was studied in the mouse by Northern blot analysis and in situ hybridization [20].
• Western blotting monitored prosaposin in cells also as a di- or trimeric form, whereas the chimeric saposins as monomeric [21].

References