{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:40:53Z","timestamp":1790505653401,"version":"4.1.0"},"reference-count":55,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T00:00:00Z","timestamp":1639699200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 108\u20102321\u2010B\u2010002 \u2010060 \u2010MY2"],"award-info":[{"award-number":["MOST 108\u20102321\u2010B\u2010002 \u2010060 \u2010MY2"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 109\u20102320\u2010B\u2010002\u2010073 \u2010"],"award-info":[{"award-number":["MOST 109\u20102320\u2010B\u2010002\u2010073 \u2010"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST\u2010110\u20102636\u2010B\u2010007\u2010005"],"award-info":[{"award-number":["MOST\u2010110\u20102636\u2010B\u2010007\u2010005"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004737","name":"National Health Research Institutes","doi-asserted-by":"publisher","award":["NHRI\u2010EX109\u201010716NC"],"award-info":[{"award-number":["NHRI\u2010EX109\u201010716NC"]}],"id":[{"id":"10.13039\/501100004737","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005762","name":"National Taiwan University Hospital","doi-asserted-by":"publisher","award":["109\u2010EDN02"],"award-info":[{"award-number":["109\u2010EDN02"]}],"id":[{"id":"10.13039\/501100005762","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005762","name":"National Taiwan University Hospital","doi-asserted-by":"publisher","award":["NTUH 109\u2010T18"],"award-info":[{"award-number":["NTUH 109\u2010T18"]}],"id":[{"id":"10.13039\/501100005762","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005762","name":"National Taiwan University Hospital","doi-asserted-by":"publisher","award":["UN109\u2010011"],"award-info":[{"award-number":["UN109\u2010011"]}],"id":[{"id":"10.13039\/501100005762","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p><jats:italic>Leucine\u2010rich repeat kinase 2<\/jats:italic> (<jats:italic>LRRK2<\/jats:italic>) is a common risk gene for Parkinson's disease (PD) and inflammatory bowel disorders. However, the penetrance of the most prevalent <jats:italic>LRRK2<\/jats:italic> mutation, G2019S, is &lt;50%. Factors other than genetic mutations are needed in PD process.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>To examine whether and how gut inflammation may act as an environmental trigger to neurodegeneration in PD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A mild and chronic dextran sodium sulfate (DSS)\u2010induced colitis mice model harboring <jats:italic>LRRK2<\/jats:italic> G2019S mutation was established. The colitis severity, immune responses, locomotor function, dopaminergic neuron, and microglia integrity were compared between littermate controls, transgenic <jats:italic>LRRK2 wild type<\/jats:italic> (<jats:italic>WT<\/jats:italic>), and <jats:italic>LRRK2 G2019S<\/jats:italic> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The <jats:italic>LRRK2 G2019S<\/jats:italic> mice are more vulnerable to DSS\u2010induced colitis than littermate controls or <jats:italic>LRRK2 WT<\/jats:italic> animals with increased intestinal expressions of pattern\u2010recognition receptors, including toll\u2010like receptors (TLRs), nuclear factor (NF)\u2010\u03baB activation, and pro\u2010inflammatory cytokines secretion, especially tumor necrosis factor (TNF)\u2010\u03b1. Notably, the colonic expression of \u03b1\u2010synuclein was significantly increased in <jats:italic>LRRK2 G2019S<\/jats:italic> colitis mice. We subsequently observed more aggravated locomotor defect, microglia activation, and dopaminergic neuron loss in <jats:italic>LRRK2 G2019S<\/jats:italic> colitis mice than control animals. Treatment with anti\u2010TNF\u2010\u03b1 monoclonal antibody, adalimumab, abrogated both gut and neuroinflammation, mitigated neurodegeneration, and improved locomotor function in <jats:italic>LRRK2 G2019S<\/jats:italic> colitis mice. Finally, we validated increased colonic expressions of LRRK2, TLRs, and NF\u2010\u03baB pathway proteins and elevated plasma TNF\u2010\u03b1 level in PD patients compared to controls, especially in those with <jats:italic>LRRK2<\/jats:italic> risk variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings demonstrate that chronic colitis promotes parkinsonism in genetically susceptible mice and TNF\u2010\u03b1 plays a detrimental role in the gut\u2010brain axis of PD. \u00a9 2021 International Parkinson and Movement Disorder Society<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.28890","type":"journal-article","created":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T08:24:40Z","timestamp":1639729480000},"page":"745-757","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Mild Chronic Colitis Triggers Parkinsonism in <scp><i>LRRK2<\/i><\/scp> Mutant Mice Through Activating <scp>TNF<\/scp>\u2010\u03b1 Pathway"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8566-7573","authenticated-orcid":false,"given":"Chin\u2010Hsien","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Neurology, National Taiwan University Hospital, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han\u2010Yi","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Taiwan University Hospital, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"En\u2010Pong","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Taiwan University Hospital, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Ci","family":"Ke","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Taiwan University Hospital, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei\u2010Fang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, National Taiwan University Hospital, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chyng\u2010Yann","family":"Shiue","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, National Taiwan University Hospital, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi\u2010Han","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, National Taiwan University Hospital, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6104-220X","authenticated-orcid":false,"given":"Peng\u2010Hsiang","family":"Liao","sequence":"additional","affiliation":[{"name":"College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela Yu\u2010Huey","family":"Hsu","sequence":"additional","affiliation":[{"name":"College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li\u2010An","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering and Environmental Sciences National Tsing Hua University  Hsinchu Taiwan"},{"name":"Brain Research Center National Tsing Hua University  Hsinchu Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya\u2010Ding","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering and Environmental Sciences National Tsing Hua University  Hsinchu Taiwan"},{"name":"Brain Research Center National Tsing Hua University  Hsinchu Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya\u2010Hui","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering and Environmental Sciences National Tsing Hua University  Hsinchu Taiwan"},{"name":"Brain Research Center National Tsing Hua University  Hsinchu Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Cheng","family":"Tai","sequence":"additional","affiliation":[{"name":"Department of Neurology E\u2010Da Hospital  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia\u2010Tung","family":"Shun","sequence":"additional","affiliation":[{"name":"Department of Pathology National Taiwan University Hospital, College of Medicine, National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han\u2010Mo","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, College of Medicine National Taiwan University  Taipei Taiwan"},{"name":"Department of Internal Medicine National Taiwan University Hospital, College of Medicine, National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming\u2010Shiang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine National Taiwan University Hospital, College of Medicine, National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,12,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000247740.47667.03"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3233\/JPD-179001"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181c34af5"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.25898"},{"issue":"1469","key":"e_1_2_10_6_1","article-title":"Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease","volume":"167","author":"Sampson TR","year":"2016","journal-title":"Cell"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28119"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-019-1528-y"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26128"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-016-0002-0"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028032"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.14802\/jmd.18067"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1223813"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.11.005"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.10.023"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.175"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/MIB.0000000000000735"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aan8162"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27059"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2020.06.027"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv453"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2010.07.010"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20467"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa279"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13550-021-00768-9"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27633"},{"key":"e_1_2_10_27_1","article-title":"NanoStringDiff: a novel statistical method for differential expression analysis based on NanoString nCounter data","volume":"44","author":"Wang H","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2018.03.006"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep14488"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.597187"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1080\/13880209.2019.1653326"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.22027"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.6b00142"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2019.00218"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5196"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/ecco-jcc\/jjw053"},{"key":"e_1_2_10_37_1","first-page":"21","article-title":"Fecal calprotectin in inflammatory bowel disease","volume":"9","author":"Walsham NE","year":"2016","journal-title":"Clin Exp Gastroenterol"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-015-0449-7"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20180463"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-316844"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2019.1611152"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep12018"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.204.Supp.226.9"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3233"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy077"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-017-0010-8"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1A0417-147RR"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2006.107904"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/6838965"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.2002.7871"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2626-6"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-017-0241-2"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19092693"},{"key":"e_1_2_10_54_1","first-page":"182","article-title":"Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease","volume":"119","author":"Brochard V","year":"2009","journal-title":"J Clin Invest"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2018.0605"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-05760-9"}],"container-title":["Movement Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mds.28890","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mds.28890","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mds.28890","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T09:57:57Z","timestamp":1760954277000},"score":1,"resource":{"primary":{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/10.1002\/mds.28890"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,17]]},"references-count":55,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["10.1002\/mds.28890"],"URL":"https:\/\/doi.org\/10.1002\/mds.28890","archive":["Portico"],"relation":{},"ISSN":["0885-3185","1531-8257"],"issn-type":[{"value":"0885-3185","type":"print"},{"value":"1531-8257","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,17]]},"assertion":[{"value":"2021-08-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-12-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}