Prosaposin: A Multifaceted Protein Orchestrating Biological Processes and Diseases

Abstract

Prosaposin (PSAP), a multifunctional protein, plays a central role in various biological processes and diseases. It is the precursor of lysosomal activating protein, which is important for lipid metabolism and glucose metabolism. PSAP is implicated in cell signaling, neuroprotection, immunomodulation, and tumorigenesis. In neurological disorders, PSAP acts as a neurotrophic factor influencing nerve cell survival and synapse growth, and its dysfunction is associated with a variety of diseases. It modulates immune responses and macrophage functions, affecting inflammation and immune cell activities. The role of PSAP in cancers is complex, because it promotes or inhibits tumor growth depending on the context and it serves as a potential biomarker for various malignancies. This review examines current research on the functional and pathological roles of PSAP, emphasizing the importance of PSAP in Gaucher disease, neurodegenerative diseases, cardiovascular diseases, and cancer. In order to develop targeted therapies for various diseases, it is essential to understand the mechanisms of action of PSAP in different biological processes.

Keywords: Alzheimer’s disease; Gaucher disease; Parkinson’s disease; atherosclerosis; cancer; prosaposin; saposins.

Figure 1

Physiological and Pathological Functions of PSAP. The C-terminus of PSAP interacts with Sortilin in the cell, transporting PSAP to the lysosome to activate Cathepsins, where it is hydrolyzed and processed by Cathepsins into four sphingolipid-activating proteins, known as Sap A–D. In terms of physiological functions, PSAP can promote synaptic growth and development through regulating α-synuclein (α-Syn) homeostasis. It inhibits cAMP/PKA signaling via binding to GPR37/GPR37L1 receptors, which plays a neuroprotective role in the nervous system. PSAP/Sap C binds to LRP receptors and Gα-coupled receptors to activate ERK, sphingosine kinase (SK), and PI3K/Akt signaling pathways, which inhibit TNFα expression and exert anti-apoptotic effects. PSAP may regulate M2 macrophage function and facilitate lysosomal antigen processing. PSAP also contributes to the regulation of the reproductive system: the C-terminal domain of PSAP interacts with Rhox5 via MAPK and PI3K/Akt signaling pathways, participating in prostasomal development, spermatogenesis, and regulation of fertilization capacity. In terms of pathological functions, PSAP inhibits Gaucher disease (GD). It affects the progression of degenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), atherosclerosis (AS), and tumor development. Created with BioRender.com. (Arrows indicate promotive effects. Blunted arrows indicate inhibitory effects. Blue arrows and blue blunted arrows indicate the biological roles of PSAP. Red arrows and red blunted arrows indicate pathological roles of PSAP).

Figure 2

PSAP in Gaucher disease (GD). Gaucher disease (GD) is primarily caused by mutations in the GBA1 gene located at chromosome 1q21. This gene encodes the lysosomal enzyme β-glucocerebrosidase (GCase), which is responsible for hydrolyzing glucosylceramide (GluCer) into glucose and ceramide. The PSAP gene encodes the precursor protein prosaposin, which is proteolytically cleaved to generate Saposin C (Sap C), one of the four saposins. Sap C regulates GCase function through the following mechanisms: (1) stabilizing the GCase protein structure to prevent degradation; (2) disrupting the lipid organization of lysosomal membranes to promote GCase binding to anionic phospholipid-enriched membrane surfaces, thereby enhancing its catalytic activity; and (3) directly participating in the hydrolysis of the substrate GluCer. When PSAP gene mutations occur (e.g., p.Pro378Arg, c.1005+1G>A splice-site variant, or biallelic deletions), Sap C production is significantly reduced or completely absent, leading to the inability of GCase to effectively bind lysosomal membranes and subsequent loss of activity. This dysfunction not only causes abnormal accumulation of GluCer but also results in widespread deposition of other sphingolipid metabolites, such as lactosylceramide (LacCer) and globotriaosylceramide (Gb3). These lipid aggregates trigger the transformation of macrophages into “Gaucher cells” (lipid-laden macrophages), which infiltrate organs such as the liver, spleen, and bone marrow, leading to anemia, thrombocytopenia, and bone damage. Additionally, Sap C deficiency disrupts axonal membrane homeostasis in the nervous system, causing progressive loss of cerebellar Purkinje cells, axonal globoid degeneration, and motor deficits (e.g., ataxia). It also activates oxidative stress and neuroinflammatory pathways, accelerating Parkinson’s disease-like neurodegenerative pathology. Created with BioRender.com.

Figure 3

PSAP in Parkinson’s disease (PD). PSAP gene variants (e.g., rs4747203, rs885828) promote Parkinson’s disease (PD) progression by impairing autophagic flux, inducing α-synuclein (α-Syn) aggregation, and disrupting lysosomal function, leading to dopaminergic neuron degeneration. PSAP is processed by Cathepsin B (CSTB) to generate Sap C; thus, PSAP deficiency or mutations reduce levels of its derivative Sap C, suppressing glucocerebrosidase (GCase) activity and exacerbating pathological α-Syn accumulation. Conversely, PSAP overexpression or pharmacological interventions (e.g., ambroxol) upregulate Sap C and LIMP-2 levels, restore GCase activity and enhance α-Syn clearance, thereby inhibiting PD pathogenesis. PSAP interacts with progranulin (PGRN) in lysosomes, mutually enhancing their transport and activation, which further potentiates GCase activity. PSAP, as an endogenous ligand of GPR37, binds to GPR37 and facilitates its translocation to neuronal membranes, forming a PSAP-GPR37-GM1 complex within GM1-enriched lipid rafts to promote cell survival. GBA gene mutations significantly increase PD risk, while Sap C antagonizes α-Syn-mediated inhibition of GCase, restoring lysosomal function. These findings highlight the therapeutic potential of targeting PSAP-related pathways. Created with BioRender.com.

Figure 4

PSAP in Alzheimer’s disease (AD). PSAP has multiple roles in Alzheimer’s disease (AD) from early Aβ pathology to late tau-mediated neurodegeneration. (A) In early stages, PSAP accumulates in dystrophic neurites surrounding Aβ plaques, where lysosomes enriched with Sap C and LAMP1 exhibit impaired hydrolase activity (e.g., absence of cathepsin-B/D), leading to lysosomal membrane permeabilization (LMP) and neuronal death. Concurrently, PSAP interacts with progranulin (PGRN) in neurons and microglia, promoting PGRN oligomerization and its pathological sequestration within Aβ plaques, thereby diminishing the neuroprotective and anti-inflammatory functions of PGRN. (B) As AD progresses to tau-dominated stages, PSAP expression declines in neurons harboring neurofibrillary tangles (NFTs), disrupting its interaction with PGRN and exacerbating tau hyperphosphorylation and aggregation, which ultimately promotes NFT formation, compromises PGRN-mediated neuroprotection and anti-inflammatory functions, and accelerates neurodegeneration and cognitive decline. (C) Therapeutic intervention with the PSAP-derived peptide PS18 counteracts Aβ toxicity by activating the PI3K/Akt pathway to suppress GSK-3β/α activity, shifting amyloid precursor protein (APP) processing toward non-amyloidogenic pathways, and enhancing hippocampal neurogenesis through regulation of progenitor cell proliferation, survival, and differentiation. PS18 further mitigates apoptosis by modulating Bcl-2/BAX balance, preserving mitochondrial integrity, and inhibiting caspase-3 activation. PSAP emerges as a critical regulator of lysosomal dysfunction, protein aggregation, and neuroinflammation, with its dual roles in early Aβ pathology and late tauopathy, highlighting its potential as a multi-target therapeutic candidate for AD. Created with BioRender.com.

Figure 5

PSAP in Atherosclerosis (AS). PSAP regulates macrophage function in atherosclerosis (AS) by a dual mechanism. (Left) Intracellularly, PSAP is processed into mature saposins by Cathepsin D (CTSD) to regulate sphingolipid degradation; its functional abnormalities (e.g., reduced CTSD activity) lead to the accumulation of glycosphingolipids and cholesterol in lysosomes, impeding ABCA1-mediated cholesterol efflux and accelerating foam cell formation. In addition, PSAP is co-expressed with APOE, APOC1, CCL2, CTSB, CTSD and MMP9, which play important roles in plaque inflammation. Furthermore, PSAP promotes macrophage inflammation via the mTOR/S6K1 pathway, and inhibition of mTOR/S6K1 reduces inflammatory responses and plaque volume in APOE^-/- mice, while PSAP deficiency suppresses macrophage glycolysis and oxidative phosphorylation to inhibit inflammatory activation of macrophages. (Right) Extracellularly, PSAP⁺ efferocytic extracellular vesicles (Effero-EVs) released by efferocytes bind to GPR37 on macrophages, activating ERK signaling and increasing c-Fos expression, which upregulates Tim4 to enhance apoptotic cell clearance. This process reduces plaque necrosis and increases collagen deposition. Advanced plaques with impaired efferocytosis exhibit necrotic core expansion and thin fibrous caps. Targeting PSAP may stabilize plaques by balancing inflammatory and efferocytic pathways. Created with BioRender.com.

Figure 6

PSAP and cancers. PSAP regulates tumor progression through diverse signaling pathways and molecular interactions. (A) In breast cancer, PSAP upregulates ERα expression via the MAPK signaling pathway, enhancing its intranuclear translocation and transcriptional activity to drive estrogen-dependent breast cancer growth. Cancer-associated fibroblasts (CAFs), differentiated under rigid extracellular matrix (ECM) conditions, secrete PSAP to activate the Akt pathway, supporting breast cancer cell proliferation while inhibiting metastasis. Additionally, the miR-23b/27b/24 cluster promotes aggressive breast cancer metastasis by directly suppressing PSAP expression. PSAP exhibits dual roles in breast cancer progression: promoting tumorigenesis in grade I tumors and suppressing metastasis in grade III tumors, highlighting its context-dependent regulatory function. (B) In ovarian cancer, inhibition of PSAP (prosaposin) by the tumor microenvironment leads to decreased secretion of thrombospondin-1 (TSP-1), enabling tumors to achieve immune evasion. The therapeutic cyclic PSAP peptide restores TSP-1 production by activating bone marrow-derived monocytes. TSP-1 binding to CD36 induces apoptosis, inhibits angiogenesis, inhibits angiogenesis, promotes macrophage infiltration, significantly suppressing tumor growth and metastasis. (C) Role of PSAP in other cancers. In prostate cancer (PCa), PSAP upregulates activity of hormone receptor (AR) and prostate-specific antigen (PSA) expression and phosphorylation, and promotes tumor growth, migration, and invasion through the integrin pathway (via β_1A-integrin, Cathepsin D [CTSD], and ceramide). Sap C further stimulates urokinase-type plasminogen activator (uPA)/uPA receptor (uPAR) and c-Jun, activates the p42/44 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) pathways, and suppresses apoptosis via Akt-mediated inhibition of caspase-3/7/9, thereby stimulating proliferation, migration, and invasion of PCa cells. (D) In gliomas and glioblastoma (GBM), PSAP promotes tumor invasion and epithelial–mesenchymal transition (EMT) through TLR4/NF-κB and TGF-β1/Smad pathways. In gastric cancer (GC) and colorectal cancer (CRC), high PSAP expression correlates with advanced tumor stages and poor prognosis, potentially promoting progression via immune microenvironment modulation. In gallbladder cancer (GBC), PSAP upregulation promotes proliferation and serves as an early diagnostic biomarker. In hepatocellular carcinoma (HCC), PSAP drives tumor proliferation via the circVAPA/miR-377-3p axis. In pancreatic ductal adenocarcinoma (PDAC), PSAP suppresses CD8⁺ T-cell infiltration to accelerate progression. In malignant pleural mesothelioma (MPM), PSAP supports tumor survival by resisting oxidative stress. In fibrosarcoma, PSAP enhances Matrix Metalloproteinase-2 (MMP-2) activity to promote invasion. Created with BioRender.com.