Work

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

Year: 2025

Type: article

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 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.

Source: npj Parkinson s Disease

DOI: 10.1038/s41531-025-01234-2

Authors: Liuyan Ding, Hui Shu, Minshan Chen, Fengchu Liang, Tingting Gan, Xingting Huang, Xingting Huang, Xiaolei Liang, Kangting Luo, Linfeng Qiu, Weiqing Huang, Xiaoqin Zhu, Xiaoyun Huang, Xiaoyun Huang, Wenlong Zhang, Pingyi Xu