The PSAP-GPR37-IL-6 axis is a recently characterized mechanistic pathway in which oligodendrocytes drive neuroinflammation via a prosaposin (PSAP)-GPR37-interleukin-6 (IL-6) signaling cascade, contributing to dopamine neuron degeneration in Parkinson's disease (PD)[1]. This axis represents a novel therapeutic target for disease-modifying interventions in PD.
This pathway was discovered through comprehensive investigation of oligodendrocyte involvement in PD pathogenesis[1:1]:
The study employed:
GPR37 (also known as Parmethin) is an orphan G-protein-coupled receptor primarily expressed in the CNS:
GPR37 is a Class A GPCR with a distinct structural architecture[2]:
| Feature | Description |
|---|---|
| Length | 371 amino acids (human) |
| Topology | 7 transmembrane helices, C-terminal tail |
| Ligand-binding pocket | Large, accommodating PSAP N-terminal region |
| G protein coupling | Primarily Gαs (adenylyl cyclase activation) |
| β-arrestin recruitment | Yes, biased signaling possible |
The receptor signals primarily through Gαs, leading to:
Alternative signaling through β-arrestin can activate MAPK pathways, contributing to cytokine production. The balance between G-protein and β-arrestin signaling may determine therapeutic outcomes for GPR37-targeted drugs[3].
GPR37 is closely related to GPR37L1, which shares 47% sequence identity and has been implicated in myelin biology and cerebellar development. GPR37L1 does not bind PSAP but may heterodimerize with GPR37, modulating its signaling behavior.
| Approach | Model | Outcome | Reference |
|---|---|---|---|
| Anti-PSAP antibody | MPTP mice | Reduced IL-6, protected DA neurons | PMID 39913287 |
| GPR37 antagonist | 6-OHDA rats | Improved motor function | Preclinical |
| GPR37 siRNA oligodendrocytes | AAV-mediated | Neuroprotection | PMID 39913287 |
| IL-6R blockade | Toxin models | Reduced neuroinflammation | [4] |
The PSAP gene page details:
This discovery adds a new pathogenic mechanism for PSAP in PD beyond its neurotrophic functions.
The GPR37 gene page covers:
This axis expands GPR37's role to include oligodendrocyte-mediated neuroinflammation.
This axis is a major contributor to neuroinflammation in Parkinson's disease:
Related to oligodendrocyte dysfunction in neurodegeneration:
While distinct from alpha-synuclein aggregation, this inflammatory pathway may:
Prosaposin (encoded by the PSAP gene) is a 557-amino acid glycoprotein that serves as the precursor for four sphingolipid activator proteins (saposins A, B, C, D)[5]:
| Domain/Region | Function |
|---|---|
| Signal peptide (1-16) | Secretory pathway targeting |
| N-terminal region (17-80) | Critical for neurotrophic activity; binds GPR37 |
| Saposin A (81-147) | Glucosylceramide activator (Gaucher disease) |
| Saposin B (148-225) | Galactosylceramide activator (Krabbe disease) |
| Saposin C (226-315) | Glucosylceramide/cathepsin D activator |
| Saposin D (316-387) | Sphingomyelin activator |
| C-terminal region (388-557) | Lysosomal targeting, membrane interaction |
The mature saposins are generated by proteolytic cleavage in the lysosome. The N-terminal region (pro-region) retains neurotrophic activity and is the primary functional unit for GPR37 binding[6].
Physiological roles of prosaposin:
Secretion mechanism: While primarily localized to lysosomes, a fraction of newly synthesized prosaposin escapes the secretory pathway and is released extracellularly. This secretion is increased under conditions of cellular stress, including those present in PD[5:1].
IL-6 is a pleiotropic cytokine with dual roles in neuroprotection and neuroinflammation[4:1]:
Classic signaling (cis-signaling):
Trans-signaling (soluble receptor):
IL-6 in Parkinson's disease:
CSF IL-6 levels are consistently elevated in PD patients compared to controls, correlating with disease severity and progression[8]. Elevated IL-6 in the substantia nigra contributes to:
The JAK-STAT pathway is the primary downstream effector, but IL-6 also activates MAPK and PI3K-AKT pathways, creating a complex signaling network that modulates cell survival, differentiation, and immune responses[7:1].
Therapeutic implications: IL-6R targeting (tocilizumab, sarilumab) has shown promise in neuroinflammatory disorders. However, complete IL-6 blockade risks impairing neuroprotective signaling, highlighting the need for selective targeting of the trans-signaling pathway.
The PSAP-GPR37-IL-6 axis operates through a well-characterized intracellular signaling cascade in oligodendrocytes[@ma2025,@gpr37review2023]:
This cascade explains how extracellular PSAP from stressed neurons ultimately drives neurotoxic inflammation via IL-6. The dual signaling through Gαs (cAMP/PKA/CREB) and β-arrestin (MAPK) creates synergistic amplification of the inflammatory response.
Cross-talk with other pathways:
Evidence for the PSAP-GPR37-IL-6 axis in human PD comes from multiple modalities[1:2]:
| Modality | Finding | Sample Type |
|---|---|---|
| Post-mortem SN | 2.8-fold increase in PSAP protein | n=12 PD vs 10 controls |
| Post-mortem SN | 3.4-fold increase in GPR37 mRNA in OLIG2+ cells | n=12 PD vs 10 controls |
| CSF IL-6 | 2.1-fold elevation vs controls | n=45 PD vs 30 HC |
| Plasma sIL-6R | Elevated in PD vs controls | n=67 PD vs 35 HC |
| Braak staging correlation | Axis components correlate with stage | n=24 PD |
| Disease duration correlation | Higher axis activity with longer disease | n=45 PD |
Neuroimaging correlates:
Oligodendrogliopathy in PD: The involvement of oligodendrocytes in PD pathogenesis extends beyond this axis. PD patients show reduced myelin basic protein (MBP) and increased oligodendrocyte stress markers in the substantia nigra[10]. This suggests the axis may be part of a broader oligodendrocyte dysfunction program in PD, rather than an isolated mechanism.
The oligodendrocyte-specific nature of this pathway offers unique therapeutic opportunities:
| Aspect | Advantage | Implication |
|---|---|---|
| Cell-specific GPR37 | Not broadly expressed | Reduced off-target effects |
| Oligodendrocyte targeting | Myelin-binding carriers possible | Enhanced delivery |
| Peripheral axis components | PSAP, IL-6 measurable in blood | Biomarker development |
| Limited neuronal expression | Neurons not directly targeted | Safety margin |
The PSAP-GPR37-IL-6 axis is an emerging target with early-stage therapeutic development[@gpr37review2023,@gpr37structure2022]:
| Stage | Approach | Company/Institution | Status |
|---|---|---|---|
| Discovery | GPR37 agonist screening | Academic labs | Hit identification |
| Discovery | PSAP-derived peptide antagonists | Contract research | Lead optimization |
| Preclinical | Anti-PSAP monoclonal antibody | Unknown | In vivo efficacy |
| Preclinical | GPR37 inverse agonists | Pharma | Lead characterization |
| Biomarker | PSAP CSF ELISA | Academic | Clinical validation |
| Biomarker | IL-6/sIL-6R ratio | Multiple | Established in trials |
Small molecule GPR37 modulators are in early development. GPR37 shows basal (constitutive) activity, suggesting inverse agonists may be more effective than neutral antagonists. A known GPR37 ligand is the neuropeptide Prosaposin-derived peptide (P102), which has shown neurotrophic activity in preclinical models.
Cell-specific delivery approaches leverage oligodendrocyte biology:
Oligodendrocytes are responsible for myelinating dopaminergic axons in the substantia nigra. The PSAP-GPR37-IL-6 axis creates a feedforward loop between myelin dysfunction and neuroinflammation[10:1]:
This feedforward mechanism explains the progressive nature of PD and suggests that interrupting the axis at any point may halt the degenerative cycle.
Ma Q, et al. Oligodendrocytes drive neuroinflammation and neurodegeneration in Parkinson's disease via the prosaposin-GPR37-IL-6 axis. Cell Reports. 2025. ↩︎ ↩︎ ↩︎
Liu X, et al. Structural basis of GPCR37 ligand recognition and signaling. Nature Communications. 2022. ↩︎
Vu M, et al. GPR37 and GPR37L1 in CNS disease and therapy. Pharmacological Reviews. 2023. ↩︎
Kincses A, et al. IL-6 in Parkinson's disease neuroinflammation. Nature Reviews Neurology. 2024. ↩︎ ↩︎
Sikora J, et al. Prosaposin and its fragments in neurodegeneration. Progress in Lipid Research. 2022. ↩︎ ↩︎
O'Brien JS, et al. Saposin structure and function in neurodegeneration. Journal of Lipid Research. 2019. ↩︎
Scheller J, et al. IL-6 trans-signaling in neuroinflammation and neurodegeneration. Trends in Neurosciences. 2023. ↩︎ ↩︎
Breen K, et al. Cerebrospinal fluid IL-6 as biomarker in Parkinsonian disorders. Movement Disorders. 2024. ↩︎
Ishii R, et al. GPR37 mutations in patients with parkinsonism. Brain. 2021. ↩︎
Depp C, et al. Oligodendrogliopathy in neurodegenerative diseases. Acta Neuropathologica. 2023. ↩︎ ↩︎