{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T18:26:56Z","timestamp":1793816816578,"version":"4.6.1"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2026,4]]},"DOI":"10.1038\/s41591-026-04262-4","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T10:01:29Z","timestamp":1774346489000},"page":"1421-1431","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["LRRK2-targeting antisense oligonucleotide in Parkinson\u2019s disease: a phase 1 randomized controlled trial"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5325-1944","authenticated-orcid":false,"given":"Omar S.","family":"Mabrouk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Tichler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Moore","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva C.","family":"Thoma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"Alexanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3493-5491","authenticated-orcid":false,"given":"Jingxian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Ying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth","family":"Hirschhorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2639-6982","authenticated-orcid":false,"given":"Roy","family":"Llorens Arenas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Annand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Unnati","family":"Kapadnis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan A.","family":"Shomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly E.","family":"Glajch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Ferber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Moroishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Czerkowicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Inra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6468-4734","authenticated-orcid":false,"given":"Ronald B.","family":"Postuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2092-9848","authenticated-orcid":false,"given":"Tanya","family":"Gurevich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1656-302X","authenticated-orcid":false,"given":"Pablo","family":"Mir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5473-3774","authenticated-orcid":false,"given":"Huw R.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Aldred","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Brodsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Ellenbogen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Larson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Tolleson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Siderowf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charalampos","family":"Tzoulis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9258-1735","authenticated-orcid":false,"given":"Ernest","family":"Balaguer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria J.","family":"Marti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0904-8201","authenticated-orcid":false,"given":"Hien T.","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly B.","family":"Kordasiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Lane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren D.","family":"Hirst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1807-1602","authenticated-orcid":false,"given":"Stephanie","family":"Fradette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle L.","family":"Graham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"4262_CR1","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.1172\/JCI24761","volume":"115","author":"L Bertram","year":"2005","unstructured":"Bertram, L. & Tanzi, R. E. The genetic epidemiology of neurodegenerative disease. J. Clin. Invest. 115, 1449\u20131457 (2005).","journal-title":"J. Clin. Invest."},{"key":"4262_CR2","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/S1474-4422(06)70471-9","volume":"5","author":"LM de Lau","year":"2006","unstructured":"de Lau, L. M. & Breteler, M. M. Epidemiology of Parkinson\u2019s disease. Lancet Neurol. 5, 525\u2013535 (2006).","journal-title":"Lancet Neurol."},{"key":"4262_CR3","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1111\/j.1468-1331.2008.02056.x","volume":"15","author":"W Poewe","year":"2008","unstructured":"Poewe, W. Non-motor symptoms in Parkinson\u2019s disease. Eur. J. Neurol. 15, 14\u201320 (2008).","journal-title":"Eur. J. Neurol."},{"key":"4262_CR4","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1002\/mds.26424","volume":"30","author":"RB Postuma","year":"2015","unstructured":"Postuma, R. B. et al. MDS clinical diagnostic criteria for Parkinson\u2019s disease. Mov. Disord. 30, 1591\u20131601 (2015).","journal-title":"Mov. Disord."},{"key":"4262_CR5","doi-asserted-by":"publisher","first-page":"S119","DOI":"10.1016\/j.parkreldis.2015.09.004","volume":"22","author":"RF Pfeiffer","year":"2016","unstructured":"Pfeiffer, R. F. Non-motor symptoms in Parkinson\u2019s disease. Parkinsonism Relat. Disord. 22, S119\u2013S122 (2016).","journal-title":"Parkinsonism Relat. Disord."},{"key":"4262_CR6","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1136\/jnnp.2007.131045","volume":"79","author":"J Jankovic","year":"2008","unstructured":"Jankovic, J. Parkinson\u2019s disease: clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatry 79, 368\u2013376 (2008).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"4262_CR7","doi-asserted-by":"publisher","first-page":"VII2","DOI":"10.1007\/s00415-006-7002-7","volume":"253","author":"W Poewe","year":"2006","unstructured":"Poewe, W. The natural history of Parkinson\u2019s disease. J. Neurol. 253, VII2\u2013VII6 (2006).","journal-title":"J. Neurol."},{"key":"4262_CR8","doi-asserted-by":"publisher","first-page":"1839","DOI":"10.1002\/mds.21030","volume":"21","author":"A Schrag","year":"2006","unstructured":"Schrag, A. & Banks, P. Time of loss of employment in Parkinson\u2019s disease. Mov. Disord. 21, 1839\u20131843 (2006).","journal-title":"Mov. Disord."},{"key":"4262_CR9","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1002\/1531-8257(200011)15:6<1112::AID-MDS1008>3.0.CO;2-A","volume":"15","author":"A Schrag","year":"2000","unstructured":"Schrag, A., Jahanshahi, M. & Quinn, N. How does Parkinson\u2019s disease affect quality of life? A comparison with quality of life in the general population. Mov. Disord. 15, 1112\u20131118 (2000).","journal-title":"Mov. Disord."},{"key":"4262_CR10","doi-asserted-by":"publisher","first-page":"1478","DOI":"10.1111\/bph.15575","volume":"179","author":"S Azeggagh","year":"2022","unstructured":"Azeggagh, S. & Berwick, D. C. The development of inhibitors of leucine-rich repeat kinase 2 (LRRK2) as a therapeutic strategy for Parkinson\u2019s disease: the current state of play. Br. J. Pharmacol. 179, 1478\u20131495 (2022).","journal-title":"Br. J. Pharmacol."},{"key":"4262_CR11","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1136\/jnnp-2019-322338","volume":"91","author":"J Jankovic","year":"2020","unstructured":"Jankovic, J. & Tan, E. K. Parkinson\u2019s disease: etiopathogenesis and treatment. J. Neurol. Neurosurg. Psychiatry 91, 795\u2013808 (2020).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"4262_CR12","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/jnc.13593","volume":"139","author":"DG Hernandez","year":"2016","unstructured":"Hernandez, D. G., Reed, X. & Singleton, A. B. Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J. Neurochem. 139, 59\u201374 (2016).","journal-title":"J. Neurochem."},{"key":"4262_CR13","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/S1474-4422(08)70117-0","volume":"7","author":"DG Healy","year":"2008","unstructured":"Healy, D. G. et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson\u2019s disease: a case-control study. Lancet Neurol. 7, 583\u2013590 (2008).","journal-title":"Lancet Neurol."},{"key":"4262_CR14","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1038\/ng.3043","volume":"46","author":"MA Nalls","year":"2014","unstructured":"Nalls, M. A. et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson\u2019s disease. Nat. Genet. 46, 989\u2013993 (2014).","journal-title":"Nat. Genet."},{"key":"4262_CR15","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/s13024-019-0344-2","volume":"14","author":"DC Berwick","year":"2019","unstructured":"Berwick, D. C., Heaton, G. R., Azeggagh, S. & Harvey, K. LRRK2 biology from structure to dysfunction: research progresses, but the themes remain the same. Mol. Neurodegener. 14, 49 (2019).","journal-title":"Mol. Neurodegener."},{"key":"4262_CR16","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.parkreldis.2022.05.012","volume":"98","author":"C Simpson","year":"2022","unstructured":"Simpson, C. et al. Prevalence of ten LRRK2 variants in Parkinson\u2019s disease: a comprehensive review. Parkinsonism Relat. Disord. 98, 103\u2013113 (2022).","journal-title":"Parkinsonism Relat. Disord."},{"key":"4262_CR17","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1038\/s41531-023-00544-7","volume":"9","author":"JM Taymans","year":"2023","unstructured":"Taymans, J. M. et al. Perspective on the current state of the LRRK2 field. npj Parkinsons Dis. 9, 104 (2023).","journal-title":"npj Parkinsons Dis."},{"key":"4262_CR18","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1016\/S1474-4422(19)30320-5","volume":"18","author":"MA Nalls","year":"2019","unstructured":"Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson\u2019s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18, 1091\u20131102 (2019).","journal-title":"Lancet Neurol."},{"key":"4262_CR19","doi-asserted-by":"publisher","first-page":"18","DOI":"10.3389\/fnmol.2016.00018","volume":"9","author":"J Nixon-Abell","year":"2016","unstructured":"Nixon-Abell, J. et al. Protective LRRK2R1398H variant enhances GTPase and Wnt signaling activity. Front. Mol. Neurosci. 9, 18 (2016).","journal-title":"Front. Mol. Neurosci."},{"key":"4262_CR20","first-page":"103","volume":"34","author":"J Trinh","year":"2022","unstructured":"Trinh, J. et al. Molecular mechanisms defining penetrance of LRRK2-associated Parkinson\u2019s disease. Med. Genet. 34, 103\u2013116 (2022).","journal-title":"Med. Genet."},{"key":"4262_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2023.167998","volume":"435","author":"CA Boecker","year":"2023","unstructured":"Boecker, C. A. The role of LRRK2 in intracellular organelle dynamics. J. Mol. Biol. 435, 167998 (2023).","journal-title":"J. Mol. Biol."},{"key":"4262_CR22","doi-asserted-by":"publisher","first-page":"e12813","DOI":"10.7554\/eLife.12813","volume":"5","author":"M Steger","year":"2016","unstructured":"Steger, M. et al. Phosphoproteomics reveals that Parkinson\u2019s disease kinase LRRK2 regulates a subset of Rab GTPases. eLife 5, e12813 (2016).","journal-title":"eLife"},{"key":"4262_CR23","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1111\/febs.15453","volume":"288","author":"Y Homma","year":"2021","unstructured":"Homma, Y., Hiragi, S. & Fukuda, M. Rab family of small GTPases: an updated view on their regulation and functions. FEBS J. 288, 36\u201355 (2021).","journal-title":"FEBS J."},{"key":"4262_CR24","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.1002\/mds.26686","volume":"31","author":"KB Fraser","year":"2016","unstructured":"Fraser, K. B. et al. Ser(P)-1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson\u2019s disease. Mov. Disord. 31, 1543\u20131550 (2016).","journal-title":"Mov. Disord."},{"key":"4262_CR25","doi-asserted-by":"publisher","first-page":"227","DOI":"10.3389\/fnins.2020.00227","volume":"14","author":"T Kuwahara","year":"2020","unstructured":"Kuwahara, T. & Iwatsubo, T. The emerging functions of LRRK2 and Rab GTPases in the endolysosomal system. Front. Neurosci. 14, 227 (2020).","journal-title":"Front. Neurosci."},{"key":"4262_CR26","doi-asserted-by":"publisher","first-page":"e31012","DOI":"10.7554\/eLife.31012","volume":"6","author":"M Steger","year":"2017","unstructured":"Steger, M. et al. Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis. eLife 6, e31012 (2017).","journal-title":"eLife"},{"key":"4262_CR27","doi-asserted-by":"publisher","first-page":"2671","DOI":"10.1042\/BCJ20160557","volume":"473","author":"G Ito","year":"2016","unstructured":"Ito, G. et al. Phos-tag analysis of Rab10 phosphorylation by LRRK2: a powerful assay for assessing kinase function and inhibitors. Biochem. J. 473, 2671\u20132685 (2016).","journal-title":"Biochem. J."},{"key":"4262_CR28","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s13024-018-0240-1","volume":"13","author":"GR Jeong","year":"2018","unstructured":"Jeong, G. R. et al. Dysregulated phosphorylation of Rab GTPases by LRRK2 induces neurodegeneration. Mol. Neurodegener. 13, 8 (2018).","journal-title":"Mol. Neurodegener."},{"key":"4262_CR29","doi-asserted-by":"crossref","unstructured":"Di Maio, R. et al. LRRK2 activation in idiopathic Parkinson\u2019s disease. Sci. Transl. Med. 10, eaar5429 (2018).","DOI":"10.1126\/scitranslmed.aar5429"},{"key":"4262_CR30","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2022.892899","volume":"16","author":"RL Wallings","year":"2022","unstructured":"Wallings, R. L. et al. WHOPPA enables parallel assessment of leucine-rich repeat kinase 2 and glucocerebrosidase enzymatic activity in Parkinson\u2019s disease monocytes. Front. Cell Neurosci. 16, 892899 (2022).","journal-title":"Front. Cell Neurosci."},{"key":"4262_CR31","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1093\/hmg\/dds470","volume":"22","author":"HJ Cho","year":"2013","unstructured":"Cho, H. J. et al. MicroRNA-205 regulates the expression of Parkinson\u2019s disease-related leucine-rich repeat kinase 2 protein. Hum. Mol. Genet. 22, 608\u2013620 (2013).","journal-title":"Hum. Mol. Genet."},{"key":"4262_CR32","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/s41531-017-0010-8","volume":"3","author":"DA Cook","year":"2017","unstructured":"Cook, D. A. et al. LRRK2 levels in immune cells are increased in Parkinson\u2019s disease. npj Parkinsons Dis. 3, 11 (2017).","journal-title":"npj Parkinsons Dis."},{"key":"4262_CR33","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1186\/s40478-016-0396-2","volume":"4","author":"C Bliederhaeuser","year":"2016","unstructured":"Bliederhaeuser, C. et al. LRRK2 contributes to monocyte dysregulation in Parkinson\u2019s disease. Acta Neuropathol. Commun. 4, 123 (2016).","journal-title":"Acta Neuropathol. Commun."},{"key":"4262_CR34","doi-asserted-by":"publisher","first-page":"526","DOI":"10.3389\/fnins.2020.00526","volume":"14","author":"OS Mabrouk","year":"2020","unstructured":"Mabrouk, O. S. et al. Quantitative measurements of LRRK2 in human cerebrospinal fluid demonstrates increased levels in G2019S patients. Front. Neurosci. 14, 526 (2020).","journal-title":"Front. Neurosci."},{"key":"4262_CR35","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202013257","volume":"13","author":"S Virreira Winter","year":"2021","unstructured":"Virreira Winter, S. et al. Urinary proteome profiling for stratifying patients with familial Parkinson\u2019s disease. EMBO Mol. Med. 13, e13257 (2021).","journal-title":"EMBO Mol. Med."},{"key":"4262_CR36","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2022.100661","volume":"3","author":"O Karayel","year":"2022","unstructured":"Karayel, O. et al. Proteome profiling of cerebrospinal fluid reveals biomarker candidates for Parkinson\u2019s disease. Cell Rep. Med. 3, 100661 (2022).","journal-title":"Cell Rep. Med."},{"key":"4262_CR37","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.neulet.2010.11.068","volume":"489","author":"L Li","year":"2011","unstructured":"Li, L. et al. Parkinson\u2019s disease involves autophagy and abnormal distribution of cathepsin L. Neurosci. Lett. 489, 62\u201367 (2011).","journal-title":"Neurosci. Lett."},{"key":"4262_CR38","doi-asserted-by":"publisher","first-page":"e2303789120","DOI":"10.1073\/pnas.2303789120","volume":"120","author":"N Yadavalli","year":"2023","unstructured":"Yadavalli, N. & Ferguson, S. M. LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition. Proc. Natl Acad. Sci. USA 120, e2303789120 (2023).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"4262_CR39","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/s41531-023-00468-2","volume":"9","author":"KM Merchant","year":"2023","unstructured":"Merchant, K. M. et al. LRRK2 and GBA1 variant carriers have higher urinary bis(monacylglycerol) phosphate concentrations in PPMI cohorts. npj Parkinsons Dis. 9, 30 (2023).","journal-title":"npj Parkinsons Dis."},{"key":"4262_CR40","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1038\/s41531-023-00482-4","volume":"9","author":"S Gomes","year":"2023","unstructured":"Gomes, S. et al. Elevated urine BMP phospholipids in LRRK2 and VPS35 mutation carriers with and without Parkinson\u2019s disease. npj Parkinsons Dis. 9, 52 (2023).","journal-title":"npj Parkinsons Dis."},{"key":"4262_CR41","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1016\/j.omtn.2017.08.002","volume":"8","author":"HT Zhao","year":"2017","unstructured":"Zhao, H. T. et al. LRRK2 antisense oligonucleotides ameliorate \u03b1-synuclein inclusion formation in a Parkinson\u2019s disease mouse model. Mol. Ther. Nucleic Acids 8, 508\u2013519 (2017).","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"4262_CR42","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abj2658","volume":"14","author":"D Jennings","year":"2022","unstructured":"Jennings, D. et al. Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson\u2019s disease. Sci. Transl. Med. 14, eabj2658 (2022).","journal-title":"Sci. Transl. Med."},{"key":"4262_CR43","doi-asserted-by":"publisher","first-page":"4209","DOI":"10.1093\/hmg\/ddr348","volume":"20","author":"MC Herzig","year":"2011","unstructured":"Herzig, M. C. et al. LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum. Mol. Genet. 20, 4209\u20134223 (2011).","journal-title":"Hum. Mol. Genet."},{"key":"4262_CR44","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1177\/01926233231205895","volume":"51","author":"GK Miller","year":"2023","unstructured":"Miller, G. K. et al. Effects of LRRK2 inhibitors in nonhuman primates. Toxicol. Pathol. 51, 232\u2013245 (2023).","journal-title":"Toxicol. Pathol."},{"key":"4262_CR45","doi-asserted-by":"publisher","first-page":"273ra215","DOI":"10.1126\/scitranslmed.aaa3634","volume":"7","author":"RN Fuji","year":"2015","unstructured":"Fuji, R. N. et al. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci. Transl. Med. 7, 273ra215 (2015).","journal-title":"Sci. Transl. Med."},{"key":"4262_CR46","doi-asserted-by":"publisher","first-page":"eaav0820","DOI":"10.1126\/scitranslmed.aav0820","volume":"12","author":"MAS Baptista","year":"2020","unstructured":"Baptista, M. A. S. et al. LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits. Sci. Transl. Med. 12, eaav0820 (2020).","journal-title":"Sci. Transl. Med."},{"key":"4262_CR47","doi-asserted-by":"publisher","first-page":"ENEURO.0453-18","DOI":"10.1523\/ENEURO.0453-18.2019","volume":"6","author":"MA Andersen","year":"2019","unstructured":"Andersen, M. A. et al. Long-term exposure to PFE-360 in the AAV-\u03b1-synuclein rat model: findings and implications. eNeuro 6, ENEURO.0453-18 (2019).","journal-title":"eNeuro"},{"key":"4262_CR48","doi-asserted-by":"publisher","first-page":"e2106685118","DOI":"10.1073\/pnas.2106685118","volume":"118","author":"Y Tian","year":"2021","unstructured":"Tian, Y. et al. LRRK2 plays essential roles in maintaining lung homeostasis and preventing the development of pulmonary fibrosis. Proc. Natl Acad. Sci. USA 118, e2106685118 (2021).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"4262_CR49","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s40035-024-00403-2","volume":"13","author":"N Lubben","year":"2024","unstructured":"Lubben, N. et al. LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression. Transl. Neurodegener. 13, 13 (2024).","journal-title":"Transl. Neurodegener."},{"key":"4262_CR50","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/s41531-023-00572-3","volume":"9","author":"D Yang","year":"2023","unstructured":"Yang, D. et al. Neurofilament light chain as a mediator between LRRK2 mutation and dementia in Parkinson\u2019s disease. npj Parkinsons Dis. 9, 132 (2023).","journal-title":"npj Parkinsons Dis."},{"key":"4262_CR51","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1038\/s41591-023-02326-3","volume":"29","author":"CJ Mummery","year":"2023","unstructured":"Mummery, C. J. et al. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer\u2019s disease: a phase 1b, randomized, placebo-controlled trial. Nat. Med. 29, 1437\u20131447 (2023).","journal-title":"Nat. Med."},{"key":"4262_CR52","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1007\/s40265-023-01904-6","volume":"83","author":"HA Blair","year":"2023","unstructured":"Blair, H. A. Tofersen: first approval. Drugs 83, 1039\u20131043 (2023).","journal-title":"Drugs"},{"key":"4262_CR53","doi-asserted-by":"publisher","first-page":"e129240","DOI":"10.1172\/jci.insight.129240","volume":"4","author":"C Mazur","year":"2019","unstructured":"Mazur, C. et al. Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging. JCI Insight 4, e129240 (2019).","journal-title":"JCI Insight"},{"key":"4262_CR54","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1093\/nar\/gkaa1235","volume":"49","author":"P Jafar-Nejad","year":"2021","unstructured":"Jafar-Nejad, P. et al. The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration. Nucleic Acids Res. 49, 657\u2013673 (2021).","journal-title":"Nucleic Acids Res."},{"key":"4262_CR55","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1007\/s00401-021-02325-z","volume":"142","author":"Y Fan","year":"2021","unstructured":"Fan, Y. et al. R1441G but not G2019S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils. Acta Neuropathol. 142, 475\u2013494 (2021).","journal-title":"Acta Neuropathol."},{"key":"4262_CR56","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.1111\/cts.13541","volume":"16","author":"M Vissers","year":"2023","unstructured":"Vissers, M. et al. A leucine-rich repeat kinase 2 (LRRK2) pathway biomarker characterization study in patients with Parkinson\u2019s disease with and without LRRK2 mutations and healthy controls. Clin. Transl. Sci. 16, 1408\u20131420 (2023).","journal-title":"Clin. Transl. Sci."},{"key":"4262_CR57","doi-asserted-by":"publisher","first-page":"E9115","DOI":"10.1073\/pnas.1812196115","volume":"115","author":"T Eguchi","year":"2018","unstructured":"Eguchi, T. et al. LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis. Proc. Natl Acad. Sci. USA 115, E9115\u2013E9124 (2018).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"4262_CR58","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1186\/s13195-019-0533-9","volume":"11","author":"S Sjodin","year":"2019","unstructured":"Sjodin, S. et al. Endo-lysosomal proteins and ubiquitin CSF concentrations in Alzheimer\u2019s and Parkinson\u2019s disease. Alzheimers Res. Ther. 11, 82 (2019).","journal-title":"Alzheimers Res. Ther."},{"key":"4262_CR59","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.105081","volume":"145","author":"T Kuwahara","year":"2020","unstructured":"Kuwahara, T. et al. Roles of lysosomotropic agents on LRRK2 activation and Rab10 phosphorylation. Neurobiol. Dis. 145, 105081 (2020).","journal-title":"Neurobiol. Dis."},{"key":"4262_CR60","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1002\/mdc3.12553","volume":"5","author":"SK Holden","year":"2018","unstructured":"Holden, S. K., Finseth, T., Sillau, S. H. & Berman, B. D. Progression of MDS-UPDRS scores over five years in de novo Parkinson disease from the Parkinson\u2019s Progression Markers Initiative cohort. Mov. Disord. Clin. Pract. 5, 47\u201353 (2018).","journal-title":"Mov. Disord. Clin. Pract."},{"key":"4262_CR61","doi-asserted-by":"publisher","first-page":"421","DOI":"10.3233\/JPD-202184","volume":"11","author":"DM Boucherie","year":"2021","unstructured":"Boucherie, D. M. et al. Parkinson\u2019s disease drug development since 1999: a story of repurposing and relative success. J. Parkinsons Dis. 11, 421\u2013429 (2021).","journal-title":"J. Parkinsons Dis."},{"key":"4262_CR62","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1081\/NCN-200060295","volume":"24","author":"BS Ross","year":"2005","unstructured":"Ross, B. S., Song, Q. & Han, M. Kilo-scale synthesis process for 2\u2032-O-(2-methoxyethyl)-pyrimidine derivatives. Nucleosides Nucleotides Nucleic Acids 24, 815\u2013818 (2005).","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"4262_CR63","doi-asserted-by":"publisher","first-page":"11577","DOI":"10.1021\/acs.joc.8b01553","volume":"83","author":"J Yang","year":"2018","unstructured":"Yang, J. et al. Solid-phase synthesis of phosphorothioate oligonucleotides using sulfurization byproducts for in situ capping. J. Org. Chem. 83, 11577\u201311585 (2018).","journal-title":"J. Org. Chem."}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04262-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04262-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04262-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T14:02:41Z","timestamp":1776780161000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04262-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,24]]},"references-count":63,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["4262"],"URL":"https:\/\/doi.org\/10.1038\/s41591-026-04262-4","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,24]]},"assertion":[{"value":"11 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"O.S.M., B.T., E.C.T., B.H., R.L.A., J.W.A., U.K., K.F., Y.M., J. Czerkowicz, S.F. and D.L.G. are employees of Biogen and may hold Biogen stocks and\/or shares. H.M.A. and J.I. are employees of Biogen. S.M.A., J. Chen, C.M.T. and E.B. declare no competing interests. T-Y.L. was employed by Biogen at the time of the study. A.A.S. was previously employed by Biogen and holds Biogen stock. K.E.G. was employed by Biogen at the time of the study, is currently an employee of Takeda and is a recipient of the ASAP grant. R.B.P. received grants from the Canadian Institute of Health Research, the Michael J. Fox Foundation, the National Institutes of Health, Roche Diagnostics and the Weston Foundation; received consulting fees from Novartis, Eisai, Merck, Vaxxinity, Bristol Myers Squibb, Ventus, Korro, Vanqua, Roche, Regeneron, Helicon, Epic, Clinilabs and AbbVie; and participates on boards for Parkinson Canada, the Michael J. Fox Foundation, the International Parkinson and Movement Disorders Society, the journal\n                      Movement Disorders\n                      and the RBD Study Group. T.G. received grant funding from the International Parkinson\u2019s Disease and Movement Disorders Society and the Parkinson\u2019s Foundation; consulting fees from AbbVie, Teva Pharmaceuticals, and Tradis Gat; honoraria from Medison; and support for attending meetings from AbbVie, Medison, AlphaMedix and Medtronic; was a co-founder of VocaVibe; participated on the advisory board for Cytora and Neurosteer; was the principal investigator of the present study (REASON trial); and received payment from Biogen for conducting the study. P.M. received financial support from the Spanish Ministry of Science and Innovation, the Instituto de Salud Carlos III\u2013Fondo Europeo de Desarrollo Regional, the Consejer\u00eda de Econom\u00eda, Innovaci\u00f3n, Ciencia y Empleo de la Junta de Andaluc\u00eda, the Consejer\u00eda de Salud y Bienestar Social de la Junta de Andaluc\u00eda and the Consejer\u00eda de Transformaci\u00f3n Econ\u00f3mica, Industria, Conocimiento y Universidades de la Junta de Andaluc\u00eda and received support for attending meetings and\/or honoraria from Abbott, Allergan, AbbVie, Bial, Britannia, Italfarmaco, Merz, UCB, Teva Pharmaceuticals and Zambon. H.R.M. received grants from PSP Association, Parkinson\u2019s UK, the UK Medical Research Council, the Cure Parkinson\u2019s Trust and the Michael J. Fox Foundation; received consulting fees from Aprinoia and AI Therapeutics; received honoraria from the Movement Disorders Society; and is a co-applicant on the patent \u201cC9ORF72 \u2013 Method for diagnosing a neurodegenerative disease (PCT\/GB2012\/052140).\u201d J.A. received funding from AbbVie, BioVie, Amneal Pharmaceuticals and IRLAB Therapeutics and received consulting fees and honoraria from AbbVie, Allergan, Boston Scientific, Teva Pharmaceuticals, US World Meds, Medtronic and Abbott. M.A.B. received consulting fees from Acadia Pharmaceuticals. A.E. received consulting fees and honoraria from AbbVie, Acorda, Ipsen, Revance, Supernus and Teva Pharmaceuticals; received consulting fees from BioVie, Cerevance, Cerevel and XW Labs; and received speaker honoraria from Arbor. D.L. received grants from the Michael J. Fox Foundation for Parkinson\u2019s Research and the Parkinson\u2019s Foundation and received speaker honoraria from Hyperkinetic Movement Disorders Tremor, Myoclonus and Chorea for the MDS-PAS Residents\u2019 School of Neurology. A.S. received grants or contracts from the National Institute of Neurological Disorders and Stroke, the National Institute on Aging and the Michael J. Fox Foundation; received consulting fees from Aspen Neuroscience, Neurocrine, Theravance, Acadia, Boehringer Ingelheim, Capsida, General Electric and Mitsubishi; and participated on advisory boards for Massachusetts General Hospital, Clintrex, PTC Therapeutics, Inhibikase, Prevail, Prilenia, Wave Therapeutics, Cerevance and Spark. C.T. received honoraria from AbbVie, Desitin, Merz, Allergan and Biogen and was listed as inventor on patent applications relating to the use of nicotinamide riboside as a treatment for PD and related disorders. These patents have been filed by the technology transfer office Vestlandets Innovasjonsselskap AS (VIS) on behalf of Haukeland University Hospital (PCT\/EP2022\/067412, PCT\/EP2023\/060962, EP4284387). M.J.M. received grants from the Michael J. Fox Foundation for Parkinson\u2019s Research and Instituto de Salud Carlos III, participated as a principal investigator for industry-sponsored clinical trials without receiving personal honoraria and has two patents planned, issued or pending, \u201cMethod for predicting\n                      L\n                      -DOPA induced dyskinesia onset and severity\u201d and \u201cDiagnostic method for multiple system atrophy.\u201d H.T.Z., H.B.K. and R.L. are employees of Ionis Pharmaceuticals and may hold Ionis stocks and\/or shares. W.D.H. was employed by Biogen, is currently employed by DaCapo Brainscience and holds stock in Biogen and DaCapo Brainscience.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}