{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nProsaposin (PSAP) is the precursor of a family of small saposin proteins (A–D) that are indispensable for lysosomal sphingolipid degradation. Saposin B, for example, extracts sulfatides from membranes to form soluble complexes that are necessary for arylsulfatase A activity, while saposin C not only forms unique oligomeric and pH‐sensitive structures to promote membrane binding but also protects key lysosomal hydrolases such as glucosylceramidase from proteolytic degradation. In addition, the proper assembly and stability of these saposins—as underscored by studies of their three‐dimensional structures, oligomerization states, and evolutionary conservation—are critical for preventing lipid storage disorders that result from PSAP deficiency."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its enzymatic cofactor role, PSAP is essential for proper lysosomal trafficking. It interacts with progranulin (PGRN) along distinct biosynthetic and endocytic routes to facilitate efficient lysosomal delivery of both proteins. Disruption of PSAP expression or its interaction with PGRN leads to severe trafficking defects, underscoring the cooperative nature of these lysosomal regulators from their earliest secretory steps in the endoplasmic reticulum."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA subset of studies has illuminated roles for PSAP‐derived saposins in the immune system. In particular, saposin C has been shown to efficiently extract lipid antigens from lysosomal membranes and to facilitate their loading onto CD1 molecules, thereby enhancing natural killer T cell recognition and immune responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPSAP is also intimately involved in cancer biology and hormone‐regulated processes. Overexpression or genomic amplification of PSAP has been reported in a variety of malignancies—including esophageal squamous cell carcinoma, prostate cancer, glioblastoma, gallbladder cancer, and breast cancer—where it functions not only as a secreted neurotrophic and growth‐promoting factor but also modulates receptor activity (such as that of the androgen and estrogen receptors) and downstream signal transduction pathways. In some contexts PSAP can impede metastatic dissemination by inducing inhibitors like thrombospondin‐1, while in other settings its regulation by microRNAs or circular RNAs contributes to increased invasive and proliferative capacities of tumor cells. In addition, PSAP’s interaction with proteases such as procath-D may further stimulate oncogenic signaling cascades."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the nervous system, variants in the PSAP gene and consequent disruptions in saposin function have been linked to neurodegenerative and lysosomal storage disorders. Associations with schizophrenia and mutations producing metachromatic leukodystrophy have been described, while rare variants in domains of PSAP—especially those affecting saposin D—are emerging as risk factors for Parkinson’s disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, studies in non‐neuronal tissues have revealed that PSAP processing is critical for other physiologic end points. In the epidermis, for instance, caspase‐14 and mesotrypsin coordinately process prosaposin to release active saposin peptides, which in turn are important for maintaining a competent skin barrier. Moreover, experimental approaches aimed at restoring saposin function in deficient cells are laying the groundwork for novel therapeutic strategies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Victoria E Ahn, Kym F Faull, Julian P Whitelegge, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Saposin C mutations in Gaucher disease patients resulting in lysosomal lipid accumulation, saposin C deficiency, but normal prosaposin processing and sorting."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddq204"}], "href": "https://doi.org/10.1093/hmg/ddq204"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20484222"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20484222"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ying Sun, Xiaoyang Qi, Gregory A Grabowski "}, {"type": "b", "children": [{"type": "t", "text": "Saposin C is required for normal resistance of acid beta-glucosidase to proteolytic degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M302752200"}], "href": "https://doi.org/10.1074/jbc.M302752200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12813057"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12813057"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ladislav Kuchar, Jana Ledvinová, Martin Hrebícek, et al. 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