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

Abstract

Neuro-immune crosstalk is increasingly recognized in Parkinson's disease (PD), and ATP13A2 is well known for its neuroprotective role. However, it remains unclear whether <i>ATP13A2</i> mutations carried by PD patients contribute to immune dysfunction that exacerbates disease progression. Here, we systematically demonstrate that many <i>ATP13A2</i> mutations result in a loss-of-expression phenotype. ATP13A2 is highly expressed in macrophages. Myeloid ATP13A2 deficiency causes uncontrolled NLRP3 inflammasome activation driven by lysosomal alkalization and subsequent disrupted mitochondrial homeostasis, rendering mice susceptible to a PD-like phenotype. PD-linked <i>ATP13A2</i> loss-of-expression mutants fail to restore the ATP13A2 levels required to suppress NLRP3 hyperactivation in ATP13A2-depleted human THP-1 monocytes. Macrophages from a PD patient carrying the <i>ATP13A2</i> loss-of-expression L927P mutation exhibit excessive NLRP3 activation due to lysosomal-mitochondrial dysfunction. Our findings provide insight into PD pathogenesis, emphasizing genetic factor-driven dysregulated macrophage NLRP3 activation, particularly in <i>ATP13A2</i> loss-of-expression mutation cases.