{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T03:22:48Z","timestamp":1792725768818,"version":"4.5.0"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"12","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,3,24]]},"abstract":"<jats:p>\n                    Neuro-immune crosstalk is increasingly recognized in Parkinson\u2019s disease (PD), and ATP13A2 is well known for its neuroprotective role. However, it remains unclear whether\n                    <jats:italic toggle=\"yes\">ATP13A2<\/jats:italic>\n                    mutations carried by PD patients contribute to immune dysfunction that exacerbates disease progression. Here, we systematically demonstrate that many\n                    <jats:italic toggle=\"yes\">ATP13A2<\/jats:italic>\n                    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\n                    <jats:italic toggle=\"yes\">ATP13A2<\/jats:italic>\n                    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\n                    <jats:italic toggle=\"yes\">ATP13A2<\/jats:italic>\n                    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\n                    <jats:italic toggle=\"yes\">ATP13A2<\/jats:italic>\n                    loss-of-expression mutation cases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2534066123","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T18:08:26Z","timestamp":1773770906000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["ATP13A2 restrains macrophage NLRP3 inflammasome activation to repress neurodegeneration via modulating mitochondrial homeostasis"],"prefix":"10.1073","volume":"123","author":[{"given":"Ziqi","family":"Zou","sequence":"first","affiliation":[{"name":"Institute of Immunology, Zhejiang University School of Medicine","place":["Hangzhou, China"]},{"name":"Liangzhu Laboratory, Zhejiang University Medical 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