Inhibition of Death-Associated Protein Kinase 1 ameliorates central and peripheral pathological changes in a mouse model of Parkinson's disease.

Abstract

BACKGROUND: Parkinson's disease (PD) is a multisystem neurodegenerative disorder affecting both the central nervous system (CNS) and the enteric nervous system (ENS). Growing evidence implicates gut-brain axis dysfunction and pathological α-synuclein (α-syn) aggregation as pivotal drivers of PD pathogenesis. Death-Associated Protein Kinase 1 (DAPK1), a pro-apoptotic serine/threonine kinase known to promote neurodegeneration and α-syn phosphorylation. yet its specific role in gut-brain axis pathology.remains unexplored. This study therefore aimed to (1) map DAPK1 expression dynamics along the gut-brain axis in PD mice, and (2) evaluate the therapeutic efficacy of DAPK1 inhibition on central/peripheral pathology. METHODS: MPTP-induced PD was modeled in C57BL/6 mice by intraperitoneal MPTP injection. Mice were stratified into: Control, MPTP, and MPTP + DAPK1 inhibitor(TC-DAPK6) groups. DAPK1 and α-syn expression in substantia nigra, stomach, small intestine, and colon were quantified by Western blot (WB) and immunohistochemistry (IHC). Histopathological alterations were assessed via H&E staining. with mucosal inflammation severity scored by Chiu score for small intestinal mucosal injury and the Geboes score for colonic mucosal injury. RESULTS: MPTP mice exhibited significant upregulation of DAPK1 and α-syn protein levels in all examined CNS and ENS tissues vs. Controls.Concomitantly, H&E staining revealed severe inflammatory damage in the small intestine and colon,validated by elevated Chiu/Geboes scores. DAPK1 inhibitor treatment: Normalized DAPK1/α-syn expression across all tissues to near-control levels;Significantly reduced intestinal inflammation, as indicated by a decline in the Chiu score in the small intestine and a decline in the Geboes score in the colon. CONCLUSION: DAPK1 drives multisystem pathology along the gut-brain axis in PD, where its overexpression promotes α-syn accumulation and intestinal inflammation. Pharmacological DAPK1 inhibition concurrently ameliorates CNS and ENS pathology,establishing it as a promising disease-modifying target for holistic PD intervention.