Effect of mutation of LRRK2-P1446L on gene expression in substantia nigra of 16 months C57BL/6 mice

In this study, we investigated the novel LRRK2 P1446L mutation and demonstrated its pivotal role in driving dopaminergic neurodegeneration through the dysregulation of death-associated protein kinase 1 (DAPK1)-mediated neuronal survival pathways.

We found that this mutation induces DAPK1 overexpression, which concurrently activates mitochondrial apoptosis and exacerbates neuroinflammation via PI3K-Akt-dependent NF-κB activation. Notably, we identified a previously unrecognized DAPK1-Tuftsin regulatory axis, wherein DAPK1 upregulation suppresses the neuroprotective peptide Tuftsin, thereby aggravating neuronal vulnerability. Our findings establish DAPK1 as a central node linking LRRK2 P1446L to multiple PD-related pathological processes, and propose combined targeting of DAPK1 activity and Tuftsin restoration as a promising therapeutic strategy for LRRK2-associated Parkinson's disease.