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Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["MJFF-022681"],"award-info":[{"award-number":["MJFF-022681"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neuroinflammation"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Parkinson\u2019s disease (PD), the second most common neurodegenerative disorder after Alzheimer\u2019s disease, and the rare disorder multiple system atrophy (MSA), are both characterized by intracellular accumulation of \u03b1-synuclein fibrils and early, sustained microglial reactivity in parallel to the neurodegeneration. Activation of the NLRP3 inflammasome in disease-associated reactive microglia is increasingly recognized as a key pathogenic driver and a promising therapeutic target in synucleinopathies. Dapansutrile (OLT1177\n                      <jats:sup>\u00ae<\/jats:sup>\n                      ) is a selective, orally bioavailable NLRP3 inhibitor with a favorable safety profile in clinical trials for non-neurological indications. Here, we evaluated the therapeutic potential of dapansutrile in preclinical models of PD and MSA and explored the predictive and translational value of its effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Two established mouse models of synucleinopathy with nigral neurodegeneration were employed: the \u03b1-synuclein preformed fibril (PFF) propagation model and the transgenic PLP-\u03b1-syn model expressing human wild-type \u03b1-synuclein in oligodendrocytes. Pharmacokinetic analyses assessed plasma and brain exposure after oral administration. The efficacy of six-month dapansutrile treatment was examined in both preventive (post-PFF injection) and therapeutic (PLP-\u03b1-syn mice) paradigms, using behavioral, histopathological, and molecular readouts. Transcriptomic profiling of striatal and midbrain microglia identified differentially expressed genes (DEGs) associated with treatment and compared them with post-mortem transcriptomic signatures of disease-associated microglia in PD patients. Plasma IL-18 and neurofilament light chain (NfL) levels were evaluated as translational biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Chronic oral dapansutrile treatment at clinically relevant doses improved motor performance, reduced \u03b1-synuclein inclusions, attenuated gliosis, and mitigated nigral neurodegeneration in both models. Microglial transcriptomic analyses revealed that dapansutrile reversed key transcriptional signatures characteristic of PD-associated reactive microglia. Moreover, plasma IL-18 and NfL levels correlated with neuropathological and functional outcomes, supporting their potential as biomarkers of target engagement and treatment efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These data identify chronic NLRP3 activation as a shared and targetable mechanism in PD and MSA and highlight dapansutrile as a CNS-penetrant, clinically advanced candidate for disease modification in \u03b1-synucleinopathies. The observed transcriptomic reprogramming of microglia and the parallel changes in blood biomarkers provide a strong translational bridge to clinical development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-026-03716-3","type":"journal-article","created":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T08:06:47Z","timestamp":1769846807000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Clinically advanced NLRP3 inhibitor modulates microglial transcriptome and alleviates \u03b1-synuclein-induced progression of parkinsonism"],"prefix":"10.1186","volume":"23","author":[{"given":"Maria","family":"Luque","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Matic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Heras-Garvin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus","family":"Amo-Aparicio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin C.","family":"Luk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela Tanja","family":"Haindl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Khalil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damaris B.","family":"Skouras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles A.","family":"Dinarello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8188-639X","authenticated-orcid":false,"given":"Nadia","family":"Stefanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,31]]},"reference":[{"key":"3716_CR1","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/S0140-6736(23)01478-2","volume":"403","author":"HR Morris","year":"2024","unstructured":"Morris HR, Spillantini MG, Sue CM, Williams-Gray CH. 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He received research grants from the Austrian MS Society, Biogen, Novartis and Roche.DBS, Chief Executive Officer of Olatec Therapeutics.CAD, Chairman of Olatec\u2019s Scientific Advisory Board, co-Chief Scientific Officer, receives compensation, and has equity in Olatec.NS, Director-at-large, Board of Directors and Chair of the Research Steering Council of Mission MSA, USA; Advisory board, Karl Golser Foundation, Italy; Advisory services for IONIS, Mitsubishi Pharma.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"76"}}