{"title":"Leucine-Rich Repeat Kinase 2 Promotes Disintegration of Retinal Pigment Epithelial Cell","authors":"Yuka Suimon , Moemi Nishimura , Miyuki Murata , Shiho Yoshida , Koichi Yokoi , Zhenyu Dong , Noriyuki Kuno , Shinobu Fujii , Zen-Ichi Tanei , Ichiro Yabe , Kousuke Noda , Susumu Ishida","doi":"10.1016/j.ajpath.2025.03.002","DOIUrl":null,"url":null,"abstract":"<div><div>Recent epidemiologic studies have shown that patients with age-related macular degeneration (AMD) have a considerably higher risk of developing Parkinson disease (PD) later in life, suggesting a possible link between these diseases. However, the common mechanisms between these two diseases remain obscure, although the pathophysiology of each has been well investigated. This study was designed to explore the shared pathologic features of AMD and PD by focusing on leucine-rich repeat kinase 2 (LRRK2) and α-synuclein, both of which play crucial roles in PD pathogenesis. Immunohistochemistry for LRRK2 and α-synuclein was performed on human eye specimens. The effect of LRRK2 on retinal pigment epithelium (RPE) cell function was investigated using the RPE cell line hTERT-RPE1. Retinal morphology and function were examined in <em>LRRK2-G2019S</em> transgenic mice, representing mutants with increased kinase activity of LRRK2. Immunohistochemistry revealed that LRRK2 and α-synuclein were present in the RPE layer of the human eye. Overexpression of LRRK2 in RPE cells increased α-synuclein and induced cell death. LRRK2 inhibited α-synuclein degradation via phosphorylation of RAB, member RAS oncogene GTPases. <em>LRRK2-G2019S</em> transgenic mice exhibited apoptosis of RPE and photoreceptors, choroidal thinning, and reduced electroretinogram amplitude, on top of α-synuclein protein accumulation in the RPE cell layer. Taken together, the current study revealed that LRRK2 is one of the key molecules involved in the common pathologic mechanisms of AMD and PD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 7","pages":"Pages 1294-1310"},"PeriodicalIF":4.7000,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0002944025001038","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Recent epidemiologic studies have shown that patients with age-related macular degeneration (AMD) have a considerably higher risk of developing Parkinson disease (PD) later in life, suggesting a possible link between these diseases. However, the common mechanisms between these two diseases remain obscure, although the pathophysiology of each has been well investigated. This study was designed to explore the shared pathologic features of AMD and PD by focusing on leucine-rich repeat kinase 2 (LRRK2) and α-synuclein, both of which play crucial roles in PD pathogenesis. Immunohistochemistry for LRRK2 and α-synuclein was performed on human eye specimens. The effect of LRRK2 on retinal pigment epithelium (RPE) cell function was investigated using the RPE cell line hTERT-RPE1. Retinal morphology and function were examined in LRRK2-G2019S transgenic mice, representing mutants with increased kinase activity of LRRK2. Immunohistochemistry revealed that LRRK2 and α-synuclein were present in the RPE layer of the human eye. Overexpression of LRRK2 in RPE cells increased α-synuclein and induced cell death. LRRK2 inhibited α-synuclein degradation via phosphorylation of RAB, member RAS oncogene GTPases. LRRK2-G2019S transgenic mice exhibited apoptosis of RPE and photoreceptors, choroidal thinning, and reduced electroretinogram amplitude, on top of α-synuclein protein accumulation in the RPE cell layer. Taken together, the current study revealed that LRRK2 is one of the key molecules involved in the common pathologic mechanisms of AMD and PD.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.