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

ABSTRACT: 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

SUBMITTER: Ding L 

PROVIDER: S-EPMC12827948 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature