{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:07:25Z","timestamp":1760058445015,"version":"build-2065373602"},"reference-count":79,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001349","name":"NMRC Clinician Scientist Individual Research","doi-asserted-by":"publisher","award":["MOH-CIRG21nov-0001","LCG002\u2013SPARK II"],"award-info":[{"award-number":["MOH-CIRG21nov-0001","LCG002\u2013SPARK II"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"Singapore Ministry of Health\u2019s National Medical Research Council","doi-asserted-by":"publisher","award":["MOH-CIRG21nov-0001","LCG002\u2013SPARK II"],"award-info":[{"award-number":["MOH-CIRG21nov-0001","LCG002\u2013SPARK II"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a neurodegenerative disorder affecting nearly 10 million people worldwide, and for which no cure is currently known. Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene, age, as well as environmental factors such as neurotoxin exposure and stress, are known to increase the risk of developing the disease in humans. To investigate the role of a specific Asian variant of the LRRK2 gene to induce susceptibility to stress and trigger PD phenotypes with time, knock-in (KI) mice bearing the human LRRK2 R1628P risk variant have been generated and studied from 2 to 16 months of age in the presence (or absence) of stress insults, including neurotoxin injections and chronic mild stress applied at 3 months of age. Pathophysiological and behavioural phenotypes have been measured at different ages and primary neurons and fibroblast cells were cultured from the KI mouse line and treated with H2O2 to study susceptibility towards oxidative stress in vitro. KI mice displayed specific PD features and these phenotypes were aggravated by environmental stresses. In particular, KI mice developed locomotion impairment and increased constipation. In addition, dopamine-related proteins were dysregulated in KI mice brains: Dopamine transporter (DAT) was decreased in the midbrain and striatum and dopamine levels were increased. Primary fibroblast cells and cortical neurons from KI mice also displayed increased susceptibility to oxidative stress. Therefore, the LRRK2 R1628P KI mice are an excellent model to study the progressive development of PD.<\/jats:p>","DOI":"10.3390\/ijms26083556","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T07:41:51Z","timestamp":1744270911000},"page":"3556","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Environmental Factors Exacerbate Parkinsonian Phenotypes in an Asian-Specific Knock-In LRRK2 Risk Variant in Mice"],"prefix":"10.3390","volume":"26","author":[{"given":"Zo\u00eb","family":"Bichler","sequence":"first","affiliation":[{"name":"Behavioural Neuroscience Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore"},{"name":"Center for Biometric Analysis, The Jackson Laboratory, Bar Harbor, ME 04609, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9114-4952","authenticated-orcid":false,"given":"Sarivin","family":"Vanan","sequence":"additional","affiliation":[{"name":"Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore"},{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore"},{"name":"Neurodegeneration Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6642-5201","authenticated-orcid":false,"given":"Qianying (Sally)","family":"Dong","sequence":"additional","affiliation":[{"name":"Behavioural Neuroscience Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8644-7839","authenticated-orcid":false,"given":"Jolene Wei Ling","family":"Lee","sequence":"additional","affiliation":[{"name":"Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore"},{"name":"Neuroscience and Behavioral Disorders Program, DUKE-NUS Graduate Medical School, Singapore 169857, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengwu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Neurodegeneration Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liting","family":"Hang","sequence":"additional","affiliation":[{"name":"Neurodegeneration Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore"},{"name":"Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, Department of Human Anatomy, Dongguan Campus, Guangdong Medical University, Dongguan 523808, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4112-4600","authenticated-orcid":false,"given":"Parasuraman","family":"Padmanabhan","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wuan Ting","family":"Saw","sequence":"additional","affiliation":[{"name":"Neuroscience and Behavioral Disorders Program, DUKE-NUS Graduate Medical School, Singapore 169857, Singapore"},{"name":"Translational Therapeutics Lab, Research Department, National Neuroscience Institute, Singapore 169856, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0251-4163","authenticated-orcid":false,"given":"Zhidong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Neuroscience and Behavioral Disorders Program, DUKE-NUS Graduate Medical School, Singapore 169857, Singapore"},{"name":"Translational Therapeutics Lab, Research Department, National Neuroscience Institute, Singapore 169856, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bal\u00e1zs","family":"Guly\u00e1s","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5440-2588","authenticated-orcid":false,"given":"Kah Leong","family":"Lim","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore"},{"name":"Neurodegeneration Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Zeng","sequence":"additional","affiliation":[{"name":"Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore"},{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore"},{"name":"Neuroscience and Behavioral Disorders Program, DUKE-NUS Graduate Medical School, Singapore 169857, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eng King","family":"Tan","sequence":"additional","affiliation":[{"name":"Neuroscience and Behavioral Disorders Program, DUKE-NUS Graduate Medical School, Singapore 169857, Singapore"},{"name":"Research Department, National Neuroscience Institute, Singapore General Hospital (SGH) Campus, Singapore 168581, Singapore"},{"name":"Department of Neurology, National Neuroscience Institute, Singapore 308433, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,10]]},"reference":[{"key":"ref_1","first-page":"504","article-title":"Parkinson\u2019s Disease and Its Management: Part 1: Disease Entity, Risk Factors, Pathophysiology, Clinical Presentation, and Diagnosis","volume":"40","author":"DeMaagd","year":"2015","journal-title":"Pharm. 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