HDCA alleviates Parkinson's disease symptoms by promoting autophagic degradation of α-synuclein in enteric neurons

Introduction

Bile acids (BAs) are emerging as key modulators of Parkinson's disease (PD) through gut-brain interactions, yet their therapeutic potential remains underutilized. While BA imbalances contribute to PD pathogenesis, the specific subspecies regulating α-synuclein (α-syn) homeostasis and their mechanisms in enteric neurons—critical sites for PD initiation—require systematic investigation.

Objective

To investigate whether hyodeoxycholic acid (HDCA), a secondary BA with documented neuroprotective properties but unproven efficacy in synucleinopathy, modulates α-syn clearance through enteric neuronal autophagy to mitigate PD progression.

Methods

A53T transgenic mice underwent behavioral assessments for PD phenotyping. State-of-the-art UPLC/MS-based metabolomics quantified BA profiles. Pharmacological interventions using target-specific inhibitors (Gly-MCA, T0070907, VER-155,008) dissected the FXR-PPARγ-HSPA8 pathway. Multiscale analyses spanning immunofluorescence, western blotting, and LC3B autophagy flux reporter assays elucidated α-syn aggregation and autophagic dynamics in primary enteric neurons.

Results

HDCA decline correlated with PD severity, positioning it as a novel biomarker for gut-brain axis dysfunction in PD. HDCA supplementation not only alleviated motor/non-motor deficits but also conferred dual neuroprotection–reducing colonic α-syn oligomers and preserving nigral dopaminergic neurons. Mechanistic decoding revealed HDCA's unparalleled capacity to activate enteric neuronal autophagy via FXR-PPARγ-HSPA8 signaling, a pathway previously unrecognized in PD therapeutics.

Conclusion

Our study reveals a novel gut-brain axis where HDCA depletion drives PD pathogenesis via FXR-PPARγ-HSPA8-mediated autophagic dysfunction in enteric neurons. PD-associated HDCA deficiency directly impairs α-syn clearance, identifying HDCA as both a gut-derived synucleinopathy biomarker and a therapeutic target.