Pathological α-synuclein propagation via the gut-liver axis induces liver injury in gut-origin Parkinson's disease mouse models.
Pathological α-synuclein propagation via the gut-liver axis induces liver injury in gut-origin Parkinson's disease mouse models.
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Original abstract
Parkinson's disease (PD) pathogenesis involves α-synuclein (α-syn) aggregation in substantia nigra. The "gut-origin hypothesis" proposes α-syn propagates from gut to brain, but its peripheral effects remain unclear. Using a gut-origin PD mouse model by intestinal wall injecting α-syn preformed fibrils (α-syn PFFs), we tracked hepatic pathology for 8 months. Hepatic α-syn pathology appeared at 6 months post-injection, hepatic senescence and inflammation were induced, with increased p16, p21, and senescence-associated secretory phenotype factors, alongside decreased LaminB1. By 8 months, proliferation markers PCNA, Ki67, SOX2 declined; fibrosis markers α-SMA, MAO-A/B, Col1α1/2, Col3α1 and hepatic hydroxyproline (HYP) rose; and serum aspartate aminotransferase (AST) and AST/ALT ratio increased, indicating liver fibrosis and dysfunction. We also detected serological indicators of liver function and fibrosis in PD patients, the serum ALT levels were significantly elevated compared to healthy controls, while AST showed a similar trend; meanwhile, hyaluronic acid (HA) and procollagen III N-terminal peptide (PIIINP) were significantly elevated compared to healthy controls, suggesting subclinical hepatic injury and fibrotic activity. We further found that hepatic TLR4/NF-κB pathway was upregulated from 6 months. In vitro, the TLR4 inhibitor mitigated α-syn PFFs-induced activation of the TLR4/NF-κB pathway, thereby alleviating hepatocyte senescence and hepatic stellate cell activation. This study provides the first evidence that gut-origin α-syn may spread to the liver, associated with senescence, inflammation, and fibrosis via triggering TLR4/NF-κB, highlighting gut-liver-brain axis in PD progression.