# Mechanistic Hypotheses: Oligodendrocyte-Driven Neuroinflammation in PD
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## Hypothesis 1: PSAP Cleavage Pattern Determines Pro-inflammatory vs. Protective Function
**Title:** Altered Prosaposin Processing Drives Neurotoxicity
**Mechanism:** Prosaposin (PSAP) is proteolytically cleaved into four saposins (Sap-A, -B, -C, -D) with distinct biological functions. We hypothesize that in PD, dysregulated cleavage (possibly by cathepsins or MMPs) generates a pathogenic cleavage pattern enriched in specific saposin fragments that disproportionately activate the PSAP-GPR37-IL-6 axis. The uncleaved propeptide may normally function as a reservoir with anti-inflammatory properties, while disease-associated proteases shunt processing toward neurotoxic fragments.
**Key Evidence:** Cathepsin D (CTSD) activity is increased in PD substantia nigra (PMID: 31722267), and CTSD can cleave PSAP. Altered saposin ratios have been implicated in Gaucher disease and related synucleinopathies (PMID: 29104288).
**Testable Prediction:** Mass spectrometry quantification of individual saposin fragments in post-mortem PD vs. age-matched control substantia nigra tissue will reveal a disease-specific cleavage signature; siRNA knockdown of candidate proteases (CTSD, MMP-2/9) in oligodendrocytes will normalize the cleavage pattern and reduce IL-6 secretion *in vitro*.
**Target Gene/Protein:** Prosaposin (PSAP)