PSAP-GPR37-IL-6 Axis in Parkinson's Disease

PSAP-GPR37-IL-6 Axis in Parkinson's Disease

Introduction

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)[@ma2025]. This axis represents a novel therapeutic target for disease-modifying interventions in PD.

Discovery and Methodology

Key Findings from PMID:39913287

This pathway was discovered through comprehensive investigation of oligodendrocyte involvement in PD pathogenesis[@ma2025]:

• PSAP secretion is increased in parkinsonian mice, particularly in the substantia nigra
• GPR37 expression is upregulated in oligodendrocytes upon PSAP exposure
• IL-6 is secreted from oligodendrocytes via a GPR37-dependent pathway
• GPR37 deficiency protects against neurodegeneration in multiple PD models
• The hallmarks of this axis are observed in patients with PD, confirming clinical relevance

Experimental Approach

The study employed:

Mouse models: Multiple PD models including toxin-based and genetic models

GPR37-deficient mice: Genetic knockout to establish protective effect

Cell-type specific analysis: Oligodendrocyte-specific GPR37 expression studies

Human post-mortem brain tissue: Validation of axis components in PD patients

The Axis Mechanism

Step-by-Step Signaling Cascade

...

PSAP-GPR37-IL-6 Axis in Parkinson's Disease

Introduction

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)[@ma2025]. This axis represents a novel therapeutic target for disease-modifying interventions in PD.

Discovery and Methodology

Key Findings from PMID:39913287

This pathway was discovered through comprehensive investigation of oligodendrocyte involvement in PD pathogenesis[@ma2025]:

• PSAP secretion is increased in parkinsonian mice, particularly in the substantia nigra
• GPR37 expression is upregulated in oligodendrocytes upon PSAP exposure
• IL-6 is secreted from oligodendrocytes via a GPR37-dependent pathway
• GPR37 deficiency protects against neurodegeneration in multiple PD models
• The hallmarks of this axis are observed in patients with PD, confirming clinical relevance

Experimental Approach

The study employed:

Mouse models: Multiple PD models including toxin-based and genetic models

GPR37-deficient mice: Genetic knockout to establish protective effect

Cell-type specific analysis: Oligodendrocyte-specific GPR37 expression studies

Human post-mortem brain tissue: Validation of axis components in PD patients

The Axis Mechanism

Step-by-Step Signaling Cascade

GPR37 (G Protein-Coupled Receptor 37)

[GPR37](/entities/gpr37) (also known as Parmethin) is an orphan G-protein-coupled receptor primarily expressed in the CNS:

• Oligodendrocyte expression: Originally characterized in neurons, GPR37 is also expressed in oligodendrocytes
• PSAP as ligand: PSAP acts as a ligand for GPR37, triggering downstream signaling
• Upregulation in PD: GPR37 expression increases in oligodendrocytes in the parkinsonian brain
• Pathogenic signaling: GPR37 activation triggers pro-inflammatory signaling cascades

GPR37 Structure and Signal Transduction {#gpr37-structure}

GPR37 is a Class A GPCR with a distinct structural architecture[@gpr37structure2022]:

| 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:

Adenylyl cyclase activation → increased cAMP

PKA activation → CREB phosphorylation and gene transcription

Transcriptional upregulation of IL-6 and other inflammatory mediators

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[@gpr37review2023].

GPR37 is closely related to [GPR37L1](/entities/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.

Evidence from PD Models

Genetic Models

• GPR37 knockout mice: Resistant to dopamine neuron loss in genetic PD models
• Oligodendrocyte-specific deficiency: Protection recapitulated with cell-type specific knockout
• No developmental defects: GPR37-deficient mice develop normally, suggesting therapeutic window

Toxin Models

• MPTP model: GPR37 deficiency protects against MPTP-induced neurodegeneration
• 6-OHDA model: Reduced lesion volume in GPR37 knockout animals
• Rotenone model: Protection against rotenone-induced dopaminergic toxicity

Human Validation

• Increased PSAP in substantia nigra of PD patients
• Elevated GPR37 in oligodendrocytes surrounding dopamine neurons
• IL-6 upregulation in PD brain tissue
• Correlation with disease severity: Axis components correlate with pathological burden

Preclinical Evidence Summary

Therapeutic Proof-of-Concept

| 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 | [@il6pd2024] |

Biomarker Potential

• PSAP levels: CSF and blood measurements correlate with disease stage
• GPR37 expression: Detectable in peripheral blood monocytes
• IL-6: Established biomarker for neuroinflammation

Integration with Existing PSAP and GPR37 Knowledge

PSAP Background

The [PSAP gene](/genes/psap) page details:

• Lysosomal function as precursor for saposins
• Associations with Gaucher disease and other lysosomal storage disorders
• Neurotrophic properties
• Previous links to PD through alpha-synuclein metabolism

This discovery adds a new pathogenic mechanism for PSAP in PD beyond its neurotrophic functions.

GPR37 Background

The [GPR37 gene](/genes/gpr37) page covers:

• Parkin substrate with E3 ubiquitin ligase regulation
• ER stress sensor function
• Previous associations with atypical parkinsonism (PSP, MSA)
• Neuronal expression and function

This axis expands GPR37's role to include oligodendrocyte-mediated neuroinflammation.

Relationship to Other PD Mechanisms

Neuroinflammation

This axis is a major contributor to [neuroinflammation in Parkinson's disease](/mechanisms/neuroinflammation-parkinsons):

• Direct inflammatory signaling through IL-6
• Oligodendrocyte activation as inflammatory cells
• Amplification of microglial activation

Oligodendrocyte Dysfunction

Related to [oligodendrocyte dysfunction in neurodegeneration](/mechanisms/oligodendrocyte-dysfunction-neurodegeneration):

• Myelin maintenance failures
• Metabolic support impairment
• Contribution to disease progression

Protein Aggregation

While distinct from [alpha-synuclein aggregation](/mechanisms/lewy-body-formation), this inflammatory pathway may:

• Accelerate protein aggregation
• Impair protein clearance mechanisms
• Contribute to prion-like propagation

Prosaposin Structure and Physiology {#psap-structure}

[Prosaposin](/entities/psap) (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)[@psapreview2022]:

| 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[@psapfragments2019].

Physiological roles of prosaposin:

• Lysosomal enzyme cofactor: Essential for hydrolysis of glycosphingolipids by lysosomal hydrolases
• Neurotrophic factor: Secreted PSAP promotes neuronal survival and neurite outgrowth
• Myelin maintenance: Saposin C is critical for Schwann cell and oligodendrocyte function
• Neuroprotection: Protective effects in models of excitotoxicity and oxidative stress

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[@psapreview2022].

Interleukin-6 Signaling in PD {#il6-signaling}

[IL-6](/entities/interleukin-6) is a pleiotropic cytokine with dual roles in neuroprotection and neuroinflammation[@il6pd2024]:

Classic signaling (cis-signaling):

• IL-6 binds membrane-bound IL-6Rα (IL6RA gene)
• IL-6Rα recruits gp130 (IL6ST gene) dimer
• JAK1/JAK2 phosphorylate gp130 cytoplasmic tail
• STAT3 enters nucleus, drives inflammatory gene expression

Trans-signaling (soluble receptor):

• Soluble IL-6Rα (sIL-6R) generated by proteolysis or alternative splicing
• sIL-6R/IL-6 complex binds gp130 on cells lacking membrane IL-6R
• Enables IL-6 responsiveness in neurons, oligodendrocytes, and endothelial cells
• Predominant pathway in neuroinflammation[@il6jaks2023]

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[@il6csf2024]. Elevated IL-6 in the substantia nigra contributes to:

• Dopamine neuron vulnerability: Chronic IL-6 exposure impairs mitochondrial function in dopaminergic neurons
• Glial activation: IL-6 polarizes microglia toward a pro-inflammatory (M1) phenotype
• Synaptic dysfunction: IL-6 disrupts excitatory amino acid transporters on astrocytes
• Blood-brain barrier permeability: IL-6 increases endothelial tight junction disassembly

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[@il6jaks2023].

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.

Detailed Signaling Cascade {#signaling-cascade}

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 Galphas (cAMP/PKA/CREB) and beta-arrestin (MAPK) creates synergistic amplification of the inflammatory response.

Cross-talk with other pathways:

• GPR37 activation can engage PI3K-AKT signaling in some contexts, potentially modulating oligodendrocyte survival
• IL-6 trans-signaling on neurons engages JAK-STAT, but can also activate MAPK and PI3K pathways
• The axis intersects with [neuroinflammation in PD](/mechanisms/neuroinflammation-parkinsons) through microglial IL-6R expression
• GPR37 is regulated by [Parkin](/entities/park2) E3 ligase activity, linking this axis to mitophagy pathways["@gpr37parkinson2021"]

Clinical Evidence in PD Patients {#clinical-evidence}

Evidence for the PSAP-GPR37-IL-6 axis in human PD comes from multiple modalities[@ma2025]:

| 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:

• DaTscan SPECT: Patients with high IL-6 show greater striatal dopamine transporter loss
• MRI volumetry: Higher IL-6 correlates with accelerated caudate/putamen atrophy
• PET (TSPO): Microglial activation (PK11195 binding) correlates with CSF IL-6

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[@oligodendrogliopathy2023]. This suggests the axis may be part of a broader oligodendrocyte dysfunction program in PD, rather than an isolated mechanism.

Therapeutic Targeting Potential

Strategies

1. PSAP Neutralization

• Anti-PSAP antibodies: Scavenge secreted PSAP before it reaches oligodendrocytes
• PSAP fragments: Blockade peptides that competitively inhibit GPR37 binding
• Small molecule inhibitors: Prevent PSAP secretion or GPR37 interaction

2. GPR37 Modulation

• GPR37 antagonists: Block PSAP-GPR37 signaling
• GPR37 inverse agonists: Reduce basal signaling activity
• Allosteric modulators: Fine-tune receptor activity

3. IL-6 Signaling Blockade

• Anti-IL-6 antibodies: Tocilizumab-style therapies
• IL-6R antagonists: Block receptor engagement
• JAK inhibitors: Inhibit downstream signaling (see [JAK-STAT pathway](/mechanisms/jak-stat-signaling-neurodegeneration))

4. Oligodendrocyte Protection

• Promyelinating therapies: Enhance myelin maintenance
• Metabolic support: Improve oligodendrocyte-neuron metabolic coupling

Challenges

• Blood-brain barrier penetration: Therapeutic antibodies must cross
• Temporal window: Intervention may need early in disease course
• Physiological functions: PSAP and IL-6 have important normal functions
• Cell-type specificity: Targeting oligodendrocytes without affecting neurons

Cell-Type Specificity Advantages

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 |

Targeting Strategies

Oligodendrocyte-specific promoters: AAV vectors with OLIG2 or MBP promoters

Myelin-traversing peptides: Exploit enhanced endocytosis in oligodendrocytes

Peripheral interception: Anti-PSAP antibodies work in blood/CSF

Research Directions

Biomarker development: Axis components as PD progression markers

Patient stratification: Identifying patients with prominent axis activation

Combination therapy: Targeting multiple points in the axis

Preventive intervention: Early targeting in at-risk individuals

Mechanism elucidation: Additional downstream effectors beyond IL-6

GPR37 structural biology: Cryo-EM structures of PSAP-bound GPR37 to inform drug design

Oligodendrocyte reprogramming: Direct conversion strategies to restore myelin homeostasis

Drug Development Pipeline {#drug-pipeline}

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)](https://pubmed.ncbi.nlm.nih.gov/30622140/), which has shown neurotrophic activity in preclinical models.

Cell-specific delivery approaches leverage oligodendrocyte biology:

• Myelin-binding domains: GPR37-targeted conjugates with myelin-affinic motifs
• MBP promoter-driven AAV: Selective expression of GPR37 antagonists in OLIG2+ cells
• Lactoferrin-based vectors: Cross the BBB and target oligodendrocytes

Integration with Myelin Biology {#myelin-integration}

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[@oligodendrogliopathy2023]:

This feedforward mechanism explains the progressive nature of PD and suggests that interrupting the axis at any point may halt the degenerative cycle.

See Also

• [Parkinson's Disease](/diseases/parkinsons-disease)
• [PSAP Gene](/entities/psap)
• [GPR37 Gene](/entities/gpr37)
• [Interleukin-6](/entities/interleukin-6)
• [Neuroinflammation in Parkinson's Disease](/mechanisms/neuroinflammation-parkinsons)
• [Oligodendrocyte Dysfunction in Neurodegeneration](/mechanisms/oligodendrocyte-dysfunction-neurodegeneration)
• [JAK-STAT Signaling in Neurodegeneration](/mechanisms/jak-stat-signaling-neurodegeneration)
• [Myelin Biology and Demyelination](/mechanisms/myelin-biology-neurodegeneration)