The LRRK2 P1446L mutation triggers dopaminergic neurodegeneration via DAPK1-mediated microglial neuroinflammation and neuronal apoptosis.

Parkinson's disease (PD) involves dopaminergic neuron loss and neuroinflammation, with leucine-rich repeat kinase 2 (LRRK2) mutations identified as major genetic risk factors. However, the pathogenic mechanism of the novel LRRK2-P1446L mutation remains unknown. Here, we designed LRRK2-P1446L mutant mice and demonstrated that the novel LRRK2-P1446L mutation drives neurodegeneration through death-associated protein kinase 1 (DAPK1) dysregulation. This mutation downregulates LRRK2 while upregulating DAPK1, which concurrently triggers microglial PI3K/Akt-dependent NF-κB activation (inducing IL-1β/IL-6/TNF-α expression) and neuronal mitochondrial apoptosis (via a Bax/Bcl-2 imbalance). Integrative multiomics revealed suppressed expression of the neuroprotective molecule tuftsin, which negatively correlated with DAPK1 expression and was linked to microbiota alterations. Our work establishes DAPK1 as a pivotal hub mediating neuroinflammation and apoptosis in LRRK2-related PD pathogenesis, and reveals novel associations with the gut-brain axis. These findings support DAPK1 inhibition as a promising therapeutic strategy, while the negative correlation with tuftsin suggests its restoration may be a potential future avenue for intervention.