{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T01:58:50Z","timestamp":1793066330685,"version":"4.5.0"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T00:00:00Z","timestamp":1743552000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T00:00:00Z","timestamp":1743552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Inflammation"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Parkinson\u2019s disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta and the abnormal aggregation of \u03b1-synuclein (\u03b1-syn). Despite extensive research, the mechanisms underlying microglial-mediated neuroinflammation and ferroptosis in PD remain inadequately understood. In particular, the role of leucine-rich repeat kinase 2 (LRRK2) in microglial cells and its modulation of the p62-Keap1-Nrf2 signaling pathway warrant further investigation.In this study, we present novel findings demonstrating that LRRK2 regulates microglial neuroinflammation and ferroptosis through the p62-Keap1-Nrf2 signaling axis in the context of PD. Using \u03b1-syn-stimulated BV2 microglial cells, we found that LRRK2 inhibition significantly reduced the production of pro-inflammatory cytokines and enhanced the activation of the p62-Keap1-Nrf2 pathway, thereby mitigating ferroptosis and oxidative stress. Furthermore, conditioned medium from LRRK2-inhibited microglia conferred neuroprotective effects on cultured neurons, highlighting the therapeutic potential of targeting LRRK2 in microglia.Importantly, these in vitro findings were corroborated in the MPTP-induced PD mouse model, where LRRK2 inhibition led to diminished microglial activation, decreased apoptosis of midbrain dopaminergic neurons, and upregulation of the p62-Keap1-Nrf2 pathway.Our study fills a critical gap in understanding the microglial mechanisms mediated by LRRK2 and provides novel insights into the pathogenesis of PD. These findings suggest that targeting LRRK2 in microglia may represent a promising therapeutic strategy for PD.<\/jats:p>","DOI":"10.1007\/s10753-025-02291-8","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T01:52:35Z","timestamp":1743731555000},"page":"3666-3691","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["LRRK2 Mediates \u03b1-Synuclein-Induced Neuroinflammation and Ferroptosis through the p62-Keap1-Nrf2 Pathway in Parkinson\u2019s Disease"],"prefix":"10.1007","volume":"48","author":[{"given":"Xinjie","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijian","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangrong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqiang","family":"Xin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinping","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongwei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longping","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guohui","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,2]]},"reference":[{"issue":"10291","key":"2291_CR1","doi-asserted-by":"publisher","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","volume":"397","author":"BR Bloem","year":"2021","unstructured":"Bloem, B.R., M.S. Okun, and C. Klein. 2021. Parkinson\u2019s disease. Lancet 397 (10291): 2284\u20132303.","journal-title":"Lancet"},{"key":"2291_CR2","doi-asserted-by":"publisher","first-page":"17013","DOI":"10.1038\/nrdp.2017.13","volume":"3","author":"W Poewe","year":"2017","unstructured":"Poewe, W., K. Seppi, C.M. Tanner, G.M. Halliday, P. Brundin, J. Volkmann, A. Schrag, and A.E. Lang. 2017. Parkinson disease. Nat Rev Dis Primers 3: 17013.","journal-title":"Parkinson disease. Nat Rev Dis Primers"},{"issue":"1","key":"2291_CR3","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s13024-020-00408-1","volume":"15","author":"K Belarbi","year":"2020","unstructured":"Belarbi, K., E. Cuvelier, M. Bonte, M. Desplanque, B. Gressier, D. Devos, and M. Chartier-Harlin. 2020. Glycosphingolipids and neuroinflammation in parkinson\u2019s disease. Molecular Neurodegeneration 15 (1): 59.","journal-title":"Molecular Neurodegeneration"},{"issue":"30","key":"2291_CR4","doi-asserted-by":"publisher","first-page":"e2303711","DOI":"10.1002\/advs.202303711","volume":"10","author":"L Yao","year":"2023","unstructured":"Yao, L., F. Lu, S. Koc, Z. Zheng, B. Wang, S. Zhang, T. Skutella, and G. Lu. 2023. Lrrk2 gly2019ser mutation promotes er stress via interacting with thbs1\/tgf-beta1 in parkinson\u2019s disease. Adv Sci (Weinh) 10 (30): e2303711.","journal-title":"Adv Sci (Weinh)"},{"issue":"15","key":"2291_CR5","doi-asserted-by":"publisher","first-page":"e2118819119","DOI":"10.1073\/pnas.2118819119","volume":"119","author":"JT Hinkle","year":"2022","unstructured":"Hinkle, J.T., J. Patel, N. Panicker, S.S. Karuppagounder, D. Biswas, B. Belingon, R. Chen, S. Brahmachari, O. Pletnikova, J.C. Troncoso, et al. 2022. Sting mediates neurodegeneration and neuroinflammation in nigrostriatal alpha-synucleinopathy. Proc Natl Acad Sci U S A 119 (15): e2118819119.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2291_CR6","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.semcdb.2019.05.004","volume":"94","author":"CS Subhramanyam","year":"2019","unstructured":"Subhramanyam, C.S., C. Wang, Q. Hu, and S.T. Dheen. 2019. Microglia-mediated neuroinflammation in neurodegenerative diseases. Seminars in Cell & Developmental Biology 94: 112\u2013120.","journal-title":"Seminars in Cell & Developmental Biology"},{"issue":"1","key":"2291_CR7","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s40035-020-00221-2","volume":"9","author":"HS Kwon","year":"2020","unstructured":"Kwon, H.S., and S. Koh. 2020. Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes. Transl Neurodegener 9 (1): 42.","journal-title":"Transl Neurodegener"},{"issue":"4","key":"2291_CR8","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/S1474-4422(09)70062-6","volume":"8","author":"EC Hirsch","year":"2009","unstructured":"Hirsch, E.C., and S. Hunot. 2009. Neuroinflammation in parkinson\u2019s disease: A target for neuroprotection? Lancet Neurology 8 (4): 382\u2013397.","journal-title":"Lancet Neurology"},{"issue":"2","key":"2291_CR9","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1002\/ana.20338","volume":"57","author":"Y Ouchi","year":"2005","unstructured":"Ouchi, Y., E. Yoshikawa, Y. Sekine, M. Futatsubashi, T. Kanno, T. Ogusu, and T. Torizuka. 2005. Microglial activation and dopamine terminal loss in early parkinson\u2019s disease. Annals of Neurology 57 (2): 168\u2013175.","journal-title":"Annals of Neurology"},{"issue":"2","key":"2291_CR10","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.4049\/jimmunol.1000208","volume":"185","author":"YC Chung","year":"2010","unstructured":"Chung, Y.C., S.R. Kim, and B.K. Jin. 2010. Paroxetine prevents loss of nigrostriatal dopaminergic neurons by inhibiting brain inflammation and oxidative stress in an experimental model of parkinson\u2019s disease. The Journal of Immunology 185 (2): 1230\u20131237.","journal-title":"The Journal of Immunology"},{"issue":"10","key":"2291_CR11","doi-asserted-by":"publisher","first-page":"6145","DOI":"10.1073\/pnas.0937239100","volume":"100","author":"D Wu","year":"2003","unstructured":"Wu, D., P. Teismann, K. Tieu, M. Vila, V. Jackson-Lewis, H. Ischiropoulos, and S. Przedborski. 2003. Nadph oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of parkinson\u2019s disease. Proc Natl Acad Sci U S A 100 (10): 6145\u20136150.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"2291_CR12","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1016\/S1474-4422(11)70175-2","volume":"10","author":"OA Ross","year":"2011","unstructured":"Ross, O.A., A.I. Soto-Ortolaza, M.G. Heckman, J.O. Aasly, N. Abahuni, G. Annesi, J.A. Bacon, S. Bardien, M. Bozi, A. Brice, et al. 2011. Association of lrrk2 exonic variants with susceptibility to parkinson\u2019s disease: A case-control study. Lancet Neurology 10 (10): 898\u2013908.","journal-title":"Lancet Neurology"},{"issue":"6","key":"2291_CR13","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1002\/acn3.51776","volume":"10","author":"YL Sosero","year":"2023","unstructured":"Sosero, Y.L., and Z. Gan-Or. 2023. Lrrk2 and parkinson\u2019s disease: From genetics to targeted therapy. Annals of Clinical Translational Neurology 10 (6): 850\u2013864.","journal-title":"Annals of Clinical Translational Neurology"},{"issue":"1","key":"2291_CR14","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1038\/s41531-021-00170-1","volume":"7","author":"MK Herrick","year":"2021","unstructured":"Herrick, M.K., and M.G. Tansey. 2021. Is lrrk2 the missing link between inflammatory bowel disease and parkinson\u2019s disease? Npj Parkinsons Dis 7 (1): 26.","journal-title":"Npj Parkinsons Dis"},{"key":"2291_CR15","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1007\/978-3-319-49969-7_7","volume":"14","author":"NL Dzamko","year":"2017","unstructured":"Dzamko, N.L. 2017. Lrrk2 and the immune system. Adv Neurobiol 14: 123\u2013143.","journal-title":"Adv Neurobiol"},{"key":"2291_CR16","doi-asserted-by":"publisher","first-page":"655819","DOI":"10.3389\/fcell.2021.655819","volume":"9","author":"L Yao","year":"2021","unstructured":"Yao, L., J. Wu, S. Koc, and G. Lu. 2021. Genetic imaging of neuroinflammation in parkinson\u2019s disease: Recent advancements. Front Cell Dev Biol 9: 655819.","journal-title":"Front Cell Dev Biol"},{"issue":"1","key":"2291_CR17","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1186\/s12868-016-0315-2","volume":"17","author":"T Maekawa","year":"2016","unstructured":"Maekawa, T., T. Sasaoka, S. Azuma, T. Ichikawa, H.L. Melrose, M.J. Farrer, and F. Obata. 2016. Leucine-rich repeat kinase 2 (lrrk2) regulates alpha-synuclein clearance in microglia. BMC Neuroscience 17 (1): 77.","journal-title":"BMC Neuroscience"},{"key":"2291_CR18","doi-asserted-by":"publisher","first-page":"661461","DOI":"10.3389\/fcell.2021.661461","volume":"9","author":"SR Oliveira","year":"2021","unstructured":"Oliveira, S.R., P.A. Dionisio, M.M. Gaspar, L. Correia Guedes, M. Coelho, M.M. Rosa, J.J. Ferreira, J.D. Amaral, and C.M.P. Rodrigues. 2021. Mir-335 targets lrrk2 and mitigates inflammation in parkinson\u2019s disease. Front Cell Dev Biol 9: 661461.","journal-title":"Front Cell Dev Biol"},{"issue":"1","key":"2291_CR19","doi-asserted-by":"publisher","first-page":"e210248","DOI":"10.1371\/journal.pone.0210248","volume":"14","author":"J Kim","year":"2019","unstructured":"Kim, J., E. Pajarillo, A. Rizor, D. Son, J. Lee, M. Aschner, and E. Lee. 2019. Lrrk2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia. PLoS ONE 14 (1): e210248.","journal-title":"PLoS ONE"},{"issue":"5","key":"2291_CR20","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.1523\/JNEUROSCI.5601-11.2012","volume":"32","author":"MS Moehle","year":"2012","unstructured":"Moehle, M.S., P.J. Webber, T. Tse, N. Sukar, D.G. Standaert, T.M. DeSilva, R.M. Cowell, and A.B. West. 2012. Lrrk2 inhibition attenuates microglial inflammatory responses. Journal of Neuroscience 32 (5): 1602\u20131611.","journal-title":"Journal of Neuroscience"},{"issue":"5","key":"2291_CR21","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","volume":"149","author":"SJ Dixon","year":"2012","unstructured":"Dixon, S.J., K.M. Lemberg, M.R. Lamprecht, R. Skouta, E.M. Zaitsev, C.E. Gleason, D.N. Patel, A.J. Bauer, A.M. Cantley, W.S. Yang, et al. 2012. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 149 (5): 1060\u20131072.","journal-title":"Cell"},{"issue":"2","key":"2291_CR22","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1038\/s41422-020-00441-1","volume":"31","author":"D Tang","year":"2021","unstructured":"Tang, D., X. Chen, R. Kang, and G. Kroemer. 2021. Ferroptosis: Molecular mechanisms and health implications. Cell Research 31 (2): 107\u2013125.","journal-title":"Cell Research"},{"key":"2291_CR23","doi-asserted-by":"publisher","first-page":"581256","DOI":"10.1155\/2014\/581256","volume":"2014","author":"S Ayton","year":"2014","unstructured":"Ayton, S., and P. Lei. 2014. Nigral iron elevation is an invariable feature of parkinson\u2019s disease and is a sufficient cause of neurodegeneration. BioMed Research International 2014: 581256.","journal-title":"BioMed Research International"},{"issue":"9","key":"2291_CR24","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1002\/mds.21020","volume":"21","author":"D Berg","year":"2006","unstructured":"Berg, D., and H. Hochstrasser. 2006. Iron metabolism in parkinsonian syndromes. Movement Disorders 21 (9): 1299\u20131310.","journal-title":"Movement Disorders"},{"issue":"3","key":"2291_CR25","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.arr.2004.01.003","volume":"3","author":"D Kaur","year":"2004","unstructured":"Kaur, D., and J. Andersen. 2004. Does cellular iron dysregulation play a causative role in parkinson\u2019s disease? Ageing Research Reviews 3 (3): 327\u2013343.","journal-title":"Ageing Research Reviews"},{"issue":"4","key":"2291_CR26","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1007\/s10534-016-9942-4","volume":"29","author":"AP Lan","year":"2016","unstructured":"Lan, A.P., J. Chen, Z.F. Chai, and Y. Hu. 2016. The neurotoxicity of iron, copper and cobalt in parkinson\u2019s disease through ros-mediated mechanisms. BioMetals 29 (4): 665\u2013678.","journal-title":"BioMetals"},{"issue":"5","key":"2291_CR27","doi-asserted-by":"publisher","first-page":"2112","DOI":"10.1046\/j.1471-4159.1998.71052112.x","volume":"71","author":"JP Spencer","year":"1998","unstructured":"Spencer, J.P., P. Jenner, S.E. Daniel, A.J. Lees, D.C. Marsden, and B. Halliwell. 1998. Conjugates of catecholamines with cysteine and gsh in parkinson\u2019s disease: Possible mechanisms of formation involving reactive oxygen species. Journal of Neurochemistry 71 (5): 2112\u20132122.","journal-title":"Journal of Neurochemistry"},{"issue":"8507","key":"2291_CR28","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1016\/S0140-6736(86)92471-2","volume":"2","author":"D Dexter","year":"1986","unstructured":"Dexter, D., C. Carter, F. Agid, Y. Agid, A.J. Lees, P. Jenner, and C.D. Marsden. 1986. Lipid peroxidation as cause of nigral cell death in parkinson\u2019s disease. Lancet 2 (8507): 639\u2013640.","journal-title":"Lancet"},{"key":"2291_CR29","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1146\/annurev-pharmtox-011112-140320","volume":"53","author":"Q Ma","year":"2013","unstructured":"Ma, Q. 2013. Role of nrf2 in oxidative stress and toxicity. Annual Review of Pharmacology and Toxicology 53: 401\u2013426.","journal-title":"Annual Review of Pharmacology and Toxicology"},{"issue":"3","key":"2291_CR30","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1152\/physrev.00023.2017","volume":"98","author":"M Yamamoto","year":"2018","unstructured":"Yamamoto, M., T.W. Kensler, and H. Motohashi. 2018. The keap1-nrf2 system: A thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiological Reviews 98 (3): 1169\u20131203.","journal-title":"Physiological Reviews"},{"issue":"3","key":"2291_CR31","doi-asserted-by":"publisher","first-page":"637","DOI":"10.14336\/AD.2018.0513","volume":"10","author":"W Tu","year":"2019","unstructured":"Tu, W., H. Wang, S. Li, Q. Liu, and H. Sha. 2019. The anti-inflammatory and anti-oxidant mechanisms of the keap1\/nrf2\/are signaling pathway in chronic diseases. Aging & Disease 10 (3): 637\u2013651.","journal-title":"Aging & Disease"},{"issue":"29","key":"2291_CR32","doi-asserted-by":"publisher","first-page":"22576","DOI":"10.1074\/jbc.M110.118976","volume":"285","author":"A Jain","year":"2010","unstructured":"Jain, A., T. Lamark, E. Sjottem, K.B. Larsen, J.A. Awuh, A. Overvatn, M. McMahon, J.D. Hayes, and T. Johansen. 2010. P62\/sqstm1 is a target gene for transcription factor nrf2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. Journal of Biological Chemistry 285 (29): 22576\u201322591.","journal-title":"Journal of Biological Chemistry"},{"issue":"7","key":"2291_CR33","doi-asserted-by":"publisher","first-page":"8648","DOI":"10.1096\/fj.201900363R","volume":"33","author":"L Yao","year":"2019","unstructured":"Yao, L., Z. Zhu, J. Wu, Y. Zhang, H. Zhang, X. Sun, C. Qian, B. Wang, L. Xie, S. Zhang, et al. 2019. Microrna-124 regulates the expression of p62\/p38 and promotes autophagy in the inflammatory pathogenesis of parkinson\u2019s disease. The FASEB Journal 33 (7): 8648\u20138665.","journal-title":"The FASEB Journal"},{"key":"2291_CR34","doi-asserted-by":"publisher","first-page":"8973509","DOI":"10.1155\/2022\/8973509","volume":"2022","author":"X Li","year":"2022","unstructured":"Li, X., J. Chen, S. Yuan, X. Zhuang, and T. Qiao. 2022. Activation of the p62-keap1-nrf2 pathway protects against ferroptosis in radiation-induced lung injury. Oxidative Medicine and Cellular Longevity 2022: 8973509.","journal-title":"Oxidative Medicine and Cellular Longevity"},{"issue":"8","key":"2291_CR35","doi-asserted-by":"publisher","first-page":"e371","DOI":"10.1038\/oncsis.2017.65","volume":"6","author":"Z Fan","year":"2017","unstructured":"Fan, Z., A. Wirth, D. Chen, C.J. Wruck, M. Rauh, M. Buchfelder, and N. Savaskan. 2017. Nrf2-keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis 6 (8): e371.","journal-title":"Oncogenesis"},{"issue":"1","key":"2291_CR36","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1002\/hep.28251","volume":"63","author":"X Sun","year":"2016","unstructured":"Sun, X., Z. Ou, R. Chen, X. Niu, D. Chen, R. Kang, and D. Tang. 2016. Activation of the p62-keap1-nrf2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 63 (1): 173\u2013184.","journal-title":"Hepatology"},{"issue":"5","key":"2291_CR37","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1016\/S1474-4422(23)00109-6","volume":"22","author":"A Siderowf","year":"2023","unstructured":"Siderowf, A., L. Concha-Marambio, D. Lafontant, C.M. Farris, Y. Ma, P.A. Urenia, H. Nguyen, R.N. Alcalay, L.M. Chahine, T. Foroud, et al. 2023. Assessment of heterogeneity among participants in the parkinson\u2019s progression markers initiative cohort using alpha-synuclein seed amplification: A cross-sectional study. Lancet Neurology 22 (5): 407\u2013417.","journal-title":"Lancet Neurology"},{"issue":"12","key":"2291_CR38","doi-asserted-by":"publisher","first-page":"111401","DOI":"10.1016\/j.celrep.2022.111401","volume":"40","author":"H Long","year":"2022","unstructured":"Long, H., S. Zhang, S. Zeng, Y. Tong, J. Liu, C. Liu, and D. Li. 2022. Interaction of rage with alpha-synuclein fibrils mediates inflammatory response of microglia. Cell Reports 40 (12): 111401.","journal-title":"Cell Reports"},{"issue":"3","key":"2291_CR39","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1007\/s00011-022-01676-x","volume":"72","author":"Q Lv","year":"2023","unstructured":"Lv, Q., K. Tao, X. Wang, X. Yao, M. Pang, J. Liu, F. Wang, and C. Liu. 2023. Role of alpha-synuclein in microglia: Autophagy and phagocytosis balance neuroinflammation in parkinson\u2019s disease. Inflammation Research 72 (3): 443\u2013462.","journal-title":"Inflammation Research"},{"issue":"5","key":"2291_CR40","doi-asserted-by":"publisher","first-page":"e31250","DOI":"10.1002\/jcp.31250","volume":"239","author":"Z Zheng","year":"2024","unstructured":"Zheng, Z., S. Zhang, X. Liu, X. Wang, C. Xue, X. Wu, X. Zhang, X. Xu, Z. Liu, L. Yao, et al. 2024. Lrrk2 regulates ferroptosis through the system xc-gsh-gpx4 pathway in the neuroinflammatory mechanism of parkinson\u2019s disease. Journal of Cellular Physiology 239 (5): e31250.","journal-title":"Journal of Cellular Physiology"},{"issue":"10","key":"2291_CR41","doi-asserted-by":"publisher","first-page":"2194","DOI":"10.1016\/j.immuni.2021.09.014","volume":"54","author":"K Borst","year":"2021","unstructured":"Borst, K., A.A. Dumas, and M. Prinz. 2021. Microglia: Immune and non-immune functions. Immunity 54 (10): 2194\u20132208.","journal-title":"Immunity"},{"issue":"1","key":"2291_CR42","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nrn2038","volume":"8","author":"ML Block","year":"2007","unstructured":"Block, M.L., L. Zecca, and J. Hong. 2007. Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms. Nature Reviews Neuroscience 8 (1): 57\u201369.","journal-title":"Nature Reviews Neuroscience"},{"key":"2291_CR43","doi-asserted-by":"crossref","unstructured":"Daniele, S.G., Beraud, D., Davenport, C., Cheng, K., Yin, H., Maguire-Zeiss, K.A. 2015. Activation of myd88-dependent tlr1\/2 signaling by misfolded alpha-synuclein, a protein linked to neurodegenerative disorders. Sci Signal 8 (376): ra45.","DOI":"10.1126\/scisignal.2005965"},{"key":"2291_CR44","doi-asserted-by":"publisher","first-page":"1562","DOI":"10.1038\/ncomms2534","volume":"4","author":"C Kim","year":"2013","unstructured":"Kim, C., D. Ho, J. Suk, S. You, S. Michael, J. Kang, S. Joong Lee, E. Masliah, D. Hwang, H. Lee, et al. 2013. Neuron-released oligomeric alpha-synuclein is an endogenous agonist of tlr2 for paracrine activation of microglia. Nature Communications 4: 1562.","journal-title":"Nature Communications"},{"key":"2291_CR45","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.freeradbiomed.2013.01.018","volume":"62","author":"DT Dexter","year":"2013","unstructured":"Dexter, D.T., and P. Jenner. 2013. Parkinson disease: From pathology to molecular disease mechanisms. Free Radical Biology & Medicine 62: 132\u2013144.","journal-title":"Free Radical Biology & Medicine"},{"issue":"6","key":"2291_CR46","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1093\/hmg\/dds522","volume":"22","author":"A Biosa","year":"2013","unstructured":"Biosa, A., A. Trancikova, L. Civiero, L. Glauser, L. Bubacco, E. Greggio, and D.J. Moore. 2013. Gtpase activity regulates kinase activity and cellular phenotypes of parkinson\u2019s disease-associated lrrk2. Human Molecular Genetics 22 (6): 1140\u20131156.","journal-title":"Human Molecular Genetics"},{"issue":"2","key":"2291_CR47","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1093\/hmg\/ddl471","volume":"16","author":"AB West","year":"2007","unstructured":"West, A.B., D.J. Moore, C. Choi, S.A. Andrabi, X. Li, D. Dikeman, S. Biskup, Z. Zhang, K. Lim, V.L. Dawson, et al. 2007. Parkinson\u2019s disease-associated mutations in lrrk2 link enhanced gtp-binding and kinase activities to neuronal toxicity. Human Molecular Genetics 16 (2): 223\u2013232.","journal-title":"Human Molecular Genetics"},{"issue":"10","key":"2291_CR48","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1038\/nn1776","volume":"9","author":"WW Smith","year":"2006","unstructured":"Smith, W.W., Z. Pei, H. Jiang, V.L. Dawson, T.M. Dawson, and C.A. Ross. 2006. Kinase activity of mutant lrrk2 mediates neuronal toxicity. Nature Neuroscience 9 (10): 1231\u20131233.","journal-title":"Nature Neuroscience"},{"key":"2291_CR49","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.nbd.2015.02.019","volume":"77","author":"E Tsika","year":"2015","unstructured":"Tsika, E., A.P.T. Nguyen, J. Dusonchet, P. Colin, B.L. Schneider, and D.J. Moore. 2015. Adenoviral-mediated expression of g2019s lrrk2 induces striatal pathology in a kinase-dependent manner in a rat model of parkinson\u2019s disease. Neurobiology of Diseases 77: 49\u201361.","journal-title":"Neurobiology of Diseases"},{"issue":"9","key":"2291_CR50","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1038\/nm.2199","volume":"16","author":"BD Lee","year":"2010","unstructured":"Lee, B.D., J. Shin, J. VanKampen, L. Petrucelli, A.B. West, H.S. Ko, Y. Lee, K.A. Maguire-Zeiss, W.J. Bowers, H.J. Federoff, et al. 2010. Inhibitors of leucine-rich repeat kinase-2 protect against models of parkinson\u2019s disease. Nature Medicine 16 (9): 998\u20131000.","journal-title":"Nature Medicine"},{"issue":"4","key":"2291_CR51","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/S1474-4422(18)30032-2","volume":"17","author":"S Liu","year":"2018","unstructured":"Liu, S., D.J. Wile, J.F. Fu, J. Valerio, E. Shahinfard, S. McCormick, R. Mabrouk, N. Vafai, J. McKenzie, N. Neilson, et al. 2018. The effect of lrrk2 mutations on the cholinergic system in manifest and premanifest stages of parkinson\u2019s disease: A cross-sectional pet study. Lancet Neurology 17 (4): 309\u2013316.","journal-title":"Lancet Neurology"},{"issue":"4","key":"2291_CR52","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1080\/01616412.2017.1286541","volume":"39","author":"X Li","year":"2017","unstructured":"Li, X., L. Su, X. Zhang, C. Zhang, L. Wang, Y. Li, Y. Zhang, T. He, X. Zhu, and L. Cui. 2017. Ulinastatin downregulates tlr4 and nf-kb expression and protects mouse brains against ischemia\/reperfusion injury. Neurological Research 39 (4): 367\u2013373.","journal-title":"Neurological Research"},{"key":"2291_CR53","doi-asserted-by":"publisher","first-page":"719807","DOI":"10.3389\/fimmu.2021.719807","volume":"12","author":"Y Li","year":"2021","unstructured":"Li, Y., Y. Xia, S. Yin, F. Wan, J. Hu, L. Kou, Y. Sun, J. Wu, Q. Zhou, J. Huang, et al. 2021. Targeting microglial alpha-synuclein\/tlrs\/nf-kappab\/nlrp3 inflammasome axis in parkinson\u2019s disease. Frontiers in Immunology 12: 719807.","journal-title":"Frontiers in Immunology"},{"key":"2291_CR54","doi-asserted-by":"publisher","first-page":"407","DOI":"10.2147\/JIR.S140188","volume":"11","author":"S Giridharan","year":"2018","unstructured":"Giridharan, S., and M. Srinivasan. 2018. Mechanisms of nf-kappab p65 and strategies for therapeutic manipulation. Journal of Inflammation Research 11: 407\u2013419.","journal-title":"Journal of Inflammation Research"},{"issue":"3","key":"2291_CR55","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.smim.2014.05.004","volume":"26","author":"MS Hayden","year":"2014","unstructured":"Hayden, M.S., and S. Ghosh. 2014. Regulation of nf-kappab by tnf family cytokines. Seminars in Immunology 26 (3): 253\u2013266.","journal-title":"Seminars in Immunology"},{"key":"2291_CR56","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/1742-2094-11-52","volume":"11","author":"I Russo","year":"2014","unstructured":"Russo, I., L. Bubacco, and E. Greggio. 2014. Lrrk2 and neuroinflammation: Partners in crime in parkinson\u2019s disease? Journal of Neuroinflammation 11: 52.","journal-title":"Journal of Neuroinflammation"},{"key":"2291_CR57","doi-asserted-by":"crossref","unstructured":"Kim, C., Beilina, A., Smith, N., Li, Y., Kim, M., Kumaran, R., Kaganovich, A., Mamais, A., Adame, A., Iba, M. et al. 2020. Lrrk2 mediates microglial neurotoxicity via nfatc2 in rodent models of synucleinopathies. Sci Transl Med 12 (565).","DOI":"10.1126\/scitranslmed.aay0399"},{"issue":"4","key":"2291_CR58","doi-asserted-by":"publisher","first-page":"e34693","DOI":"10.1371\/journal.pone.0034693","volume":"7","author":"B Kim","year":"2012","unstructured":"Kim, B., M. Yang, D. Choi, J. Kim, H. Kim, W. Seol, S. Choi, I. Jou, E. Kim, and E. Joe. 2012. Impaired inflammatory responses in murine lrrk2-knockdown brain microglia. PLoS ONE 7 (4): e34693.","journal-title":"PLoS ONE"},{"issue":"3","key":"2291_CR59","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1016\/j.cell.2016.09.030","volume":"167","author":"J Moscat","year":"2016","unstructured":"Moscat, J., M. Karin, and M.T. Diaz-Meco. 2016. P62 in cancer: Signaling adaptor beyond autophagy. Cell 167 (3): 606\u2013609.","journal-title":"Cell"},{"issue":"11","key":"2291_CR60","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1080\/15548627.2020.1712108","volume":"16","author":"DH Lee","year":"2020","unstructured":"Lee, D.H., J.S. Park, Y.S. Lee, J. Han, D. Lee, S.W. Kwon, D.H. Han, Y. Lee, and S.H. Bae. 2020. Sqstm1\/p62 activates nfe2l2\/nrf2 via ulk1-mediated autophagic keap1 degradation and protects mouse liver from lipotoxicity. Autophagy 16 (11): 1949\u20131973.","journal-title":"Autophagy"},{"key":"2291_CR61","doi-asserted-by":"publisher","first-page":"103456","DOI":"10.1016\/j.ebiom.2021.103456","volume":"69","author":"K Hou","year":"2021","unstructured":"Hou, K., J. Shen, J. Yan, C. Zhai, J. Zhang, J. Pan, Y. Zhang, Y. Jiang, Y. Wang, R.Z. Lin, et al. 2021. Loss of trim21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin. eBioMedicine 69: 103456.","journal-title":"eBioMedicine"},{"issue":"33","key":"2291_CR62","doi-asserted-by":"publisher","first-page":"9671","DOI":"10.1021\/acs.jafc.1c03751","volume":"69","author":"Y Zhao","year":"2021","unstructured":"Zhao, Y., J. Lu, A. Mao, R. Zhang, and S. Guan. 2021. Autophagy inhibition plays a protective role in ferroptosis induced by alcohol via the p62-keap1-nrf2 pathway. Journal of Agriculture and Food Chemistry 69 (33): 9671\u20139683.","journal-title":"Journal of Agriculture and Food Chemistry"},{"key":"2291_CR63","doi-asserted-by":"publisher","first-page":"310","DOI":"10.3389\/fnmol.2018.00310","volume":"11","author":"SZA Shah","year":"2018","unstructured":"Shah, S.Z.A., D. Zhao, T. Hussain, N. Sabir, M.H. Mangi, and L. Yang. 2018. P62-keap1-nrf2-are pathway: A contentious player for selective targeting of autophagy, oxidative stress and mitochondrial dysfunction in prion diseases. Frontiers in Molecular Neuroscience 11: 310.","journal-title":"Frontiers in Molecular Neuroscience"},{"issue":"4","key":"2291_CR64","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1023\/B:JOBB.0000041771.66775.d5","volume":"36","author":"S Przedborski","year":"2004","unstructured":"Przedborski, S., K. Tieu, C. Perier, and M. Vila. 2004. Mptp as a mitochondrial neurotoxic model of parkinson\u2019s disease. Journal of Bioenergetics and Biomembranes 36 (4): 375\u2013379.","journal-title":"Journal of Bioenergetics and Biomembranes"},{"issue":"1","key":"2291_CR65","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/nprot.2006.342","volume":"2","author":"V Jackson-Lewis","year":"2007","unstructured":"Jackson-Lewis, V., and S. Przedborski. 2007. Protocol for the mptp mouse model of parkinson\u2019s disease. Nature Protocols 2 (1): 141\u2013151.","journal-title":"Nature Protocols"},{"issue":"8","key":"2291_CR66","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/S0165-6147(03)00176-7","volume":"24","author":"HM Gao","year":"2003","unstructured":"Gao, H.M., B. Liu, W. Zhang, and J.S. Hong. 2003. Novel anti-inflammatory therapy for parkinson\u2019s disease. Trends in Pharmacological Sciences 24 (8): 395\u2013401.","journal-title":"Trends in Pharmacological Sciences"},{"issue":"7","key":"2291_CR67","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1042\/BCJ20170699","volume":"475","author":"AF Kalogeropulou","year":"2018","unstructured":"Kalogeropulou, A.F., J. Zhao, M.F. Bolliger, A. Memou, S. Narasimha, T.P. Molitor, W.H. Wilson, H.J. Rideout, and R.J. Nichols. 2018. P62\/sqstm1 is a novel leucine-rich repeat kinase 2 (lrrk2) substrate that enhances neuronal toxicity. The Biochemical Journal 475 (7): 1271\u20131293.","journal-title":"The Biochemical Journal"},{"issue":"9","key":"2291_CR68","doi-asserted-by":"publisher","first-page":"e163029","DOI":"10.1371\/journal.pone.0163029","volume":"11","author":"S Park","year":"2016","unstructured":"Park, S., S. Han, I. Choi, B. Kim, S.P. Park, E. Joe, and Y.H. Suh. 2016. Interplay between leucine-rich repeat kinase 2 (lrrk2) and p62\/sqstm-1 in selective autophagy. PLoS ONE 11 (9): e163029.","journal-title":"PLoS ONE"}],"container-title":["Inflammation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10753-025-02291-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10753-025-02291-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10753-025-02291-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T17:04:46Z","timestamp":1762880686000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10753-025-02291-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,2]]},"references-count":68,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["2291"],"URL":"https:\/\/doi.org\/10.1007\/s10753-025-02291-8","relation":{},"ISSN":["1573-2576"],"issn-type":[{"value":"1573-2576","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,2]]},"assertion":[{"value":"3 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 February 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 March 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 April 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical Considerations and Animal Welfare All experimental procedures involving animals were conducted in strict adherence to the guidelines outlined in the National Institutes of Health\u2019s Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85\u201323, revised 1996). The study protocol was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the First Affiliated Hospital of Nanchang Capital [Ethics Approval No. (2023)CDYFYYLK(05\u2013017)]. It should be noted that this study did not involve human subjects, and therefore, human ethics approval was not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"All authors made substantial contributions to the conception, design, and execution of the experiments described herein. Each author participated in drafting the article and critically revising it for important intellectual content. All authors provided final approval of the version to be published, and agree to be accountable for all aspects of the work.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate and Publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}]}}