Journal: Journal of Molecular Medicine (Berlin, Germany)

Article Title: Prosaposin in CNS health and disease, metabolic stress and exercise adaptation

doi: 10.1007/s00109-026-02643-3

Figure Lengend Snippet: Dual roles of prosaposin (PSAP) in the central nervous system (CNS) homeostasis: protective versus maladaptive outcomes. This schematic illustrates the opposing roles of PSAP in CNS physiology. The central axis denotes PSAP-GPR37/GPR37L1 receptor signaling as a critical regulatory hub. Left panel—protective role (green): PSAP maintains homeostasis through multiple mechanisms, including lipid metabolism and lysosomal clearance (supported by PSAP knockout studies in mice), neuroprotection via GPR37/GPR37L1 receptor activation, and clearance of pathological proteins such as α-synuclein, tau, and Aβ. PSAP also promotes neurite outgrowth and axonal regeneration (e.g., TX14(A)-induced ERK signaling), prevents ferroptosis (via suppression of ROS and iron buildup), and is essential for CNS development and myelination. Right panel—pathogenic/maladaptive role (red): Elevated or dysregulated PSAP, when it is unable to function, may disrupt homeostasis, contributing to neuroinflammation (e.g., IL-6-driven microglial activation), glioma progression (via TGF-β1/Smad and NF-κB pathways), lysosomal dysfunction from toxic accumulation, and A1 astrocyte-driven synaptic toxicity. PSAP expression may be related to aging, and may exhibit region-specific and conflicting effects in Parkinson’s disease. Abbreviations: Aβ, amyloid beta; CRISPR, clustered regularly interspaced short palindromic repeats; ERK, extracellular signal-regulated kinase; GPR37, G protein-coupled receptor 37; GPR37L1, G protein-coupled receptor 37-like 1; KO, knockout; NFYB-1, nuclear transcription factor Y beta subunit 1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PD, Parkinson’s disease; ROS, reactive oxygen species, TGF-β1, transforming growth factor beta 1. Created with BioRender.com

Article Snippet: 36152140 , Kojima et al. , 2022 , UK , In vitro: SH-SY5Y , Parkinson’s disease , PSAP; Sap C; TX14(A) , PSAP plasmid was overexpressed in cells (transfection). Flow-through assay (vesicles): TX14(A) or Saposin C were incubated in presence of fresh lipid vesicles , TX14(A) of saposin C: 5 uM , TX14(A) was obtained from Synpeptide and confirmed by mass-spectrometry. Saposin C was expressed in E. coli DE3 cells and purified from cell pellets , 1) Overexpressing PSAP in SH-SY5Y cells reduced a-synuclein levels (western blots) in a GCase activity independent manner, and PSAP-GFP was targeted to the lysosome (live-cell imaging) 2) PSAP-GFP colocalized with RAB5 and RAB7, indicating PSAP secretion into culture medium 3) PSAP overexpression promoted GCase activity without altering GCase expression levels 4) PSAP overexpression did not alter p62 (autophagy marker), but it did increase the autophagosome markers LC3-II and LC3-II/LC3-1 ratio (though these increases were less than what was observed in EGFP overexpression cells) 5) PSAP knockdown increased a-synuclein and decreased SNCA mRNA levels, suggesting feedback inhibition on SNCA transcription 6) Sap C removed a-synuclein from artificial glucosylceramide-enriched lipid vesicles at the lysosomal pH, but TX14(A) did not have this effect.

Techniques: Knock-Out, Activation Assay, Expressing, CRISPR

Journal: Journal of Molecular Medicine (Berlin, Germany)

Article Title: Prosaposin in CNS health and disease, metabolic stress and exercise adaptation

doi: 10.1007/s00109-026-02643-3

Figure Lengend Snippet: Overview of prosaptide peptides derived from the saposin C domain of prosaposin (PSAP) and their tested therapeutic applications. The full saposin C sequence is shown at the top, with the neurotrophic region ( LIDNNKTEKEIL ) highlighted in green and underlined. Left panel: Sequences of various bioengineered or truncated prosaptide peptides tested in previous studies. Conservative amino acid substitutions (*) and lysine deletions (-) are indicated. Bioactivity is noted where tested. Right panel: Mapping of each prosaptide or full saposin (A–D) to specific disease-relevant therapeutic conditions, including oxidative stress, trauma/injury, ischemia, synucleinopathies, diabetes, allodynia, drug-induced toxicity, and Alzheimer’s disease-related Aβ/tau pathology. Checkboxes indicate whether the peptide has been evaluated in vitro, in vivo, or both. Peptides derived from the neurotrophic region, such as TX14(A), 769, and PS18, show diverse functional relevance across multiple disease models. Created with BioRender.com

Article Snippet: 36152140 , Kojima et al. , 2022 , UK , In vitro: SH-SY5Y , Parkinson’s disease , PSAP; Sap C; TX14(A) , PSAP plasmid was overexpressed in cells (transfection). Flow-through assay (vesicles): TX14(A) or Saposin C were incubated in presence of fresh lipid vesicles , TX14(A) of saposin C: 5 uM , TX14(A) was obtained from Synpeptide and confirmed by mass-spectrometry. Saposin C was expressed in E. coli DE3 cells and purified from cell pellets , 1) Overexpressing PSAP in SH-SY5Y cells reduced a-synuclein levels (western blots) in a GCase activity independent manner, and PSAP-GFP was targeted to the lysosome (live-cell imaging) 2) PSAP-GFP colocalized with RAB5 and RAB7, indicating PSAP secretion into culture medium 3) PSAP overexpression promoted GCase activity without altering GCase expression levels 4) PSAP overexpression did not alter p62 (autophagy marker), but it did increase the autophagosome markers LC3-II and LC3-II/LC3-1 ratio (though these increases were less than what was observed in EGFP overexpression cells) 5) PSAP knockdown increased a-synuclein and decreased SNCA mRNA levels, suggesting feedback inhibition on SNCA transcription 6) Sap C removed a-synuclein from artificial glucosylceramide-enriched lipid vesicles at the lysosomal pH, but TX14(A) did not have this effect.

Techniques: Derivative Assay, Sequencing, In Vitro, In Vivo, Functional Assay