ATP13A2 restrains macrophage NLRP3 activation to repress neurodegeneration via modulating mitochondrial homeostasis 9349

Abstract Description Neuro-immune crosstalk has become increasingly recognized in Parkinson’s disease (PD). ATP13A2, a key genetic factor associated with PD, is well-known for its critical neuroprotective role. However, it remains unclear whether mutations in the ATP13A2 gene, found in PD patients, contribute to immune dysfunction that exacerbates disease progression. Here, we systematically demonstrate that a significant proportion of ATP13A2 mutations display a loss-of-expression phenotype. ATP13A2 is highly expressed in macrophages. Myeloid-specific ATP13A2 deficiency leads to uncontrolled NLRP3 inflammasome activation, driven by lysosomal alkalization and subsequent disrupted mitochondrial homeostasis, rendering mice more susceptible to a PD-like phenotype. PD-linked ATP13A2 loss-of-expression mutants fail to restore the ATP13A2 levels to suppress NLRP3 hyperactivation in stable ATP13A2-depleted human THP-1 monocytes. Notably, macrophages derived from a PD patient carrying the ATP13A2 loss-of-expression L927P mutation exhibit excessive NLRP3 activation due to lysosomal and mitochondrial dysfunction. Our findings provide insights into the PD pathogenesis, emphasizing genetic factor-driven dysregulated macrophage NLRP3 activation, particularly in cases involving ATP13A2 loss-of-expression mutations. Funding Sources The work was funded by the National Natural Science Foundation of China (82171719, 32100696, 81930041, U22A20307), the Natural Science Foundation of Zhejiang Province (Y23H100011), and the National Key Research and Development Program of China (STI2030-Major Projects- 2021ZD0202400, and 2022YFA1103800). Topic Categories Neuroimmunology (NEUR)