科技部新聞稿

早衰症與纖毛異常有關—

臺灣研究團隊亮眼成果獲選為EMBO Reports封面故事

日期：109年10月12日

發稿單位：生命科學研究發展司

聯絡人：李慧欣博士

電話：(02)2737-7461

E-mail：hhlee@nstc.gov.tw

科技部長期深耕基礎研究，支持國內研究人員進行各項科學研究，補助優質團隊追求學術卓越，在生命科學領域探究生命奧秘、找尋疾病機轉，進而創造科技突破造福人群。本次成果即是在科技部長期補助下，由國立陽明大學生化暨分子生物研究所陳鴻震講座教授研究團隊，與國家衛生研究院生技與藥物研究所紀雅惠副研究員合作發現，細胞初級纖毛（primary cilium）的異常可能是導致罕見疾病「早衰症」重要的致病機轉，這個發現提供一個開發早衰症治療策略的新思維。這項傑出研究成果榮登歐洲分子生物學組織雜誌（EMBO Reports），並獲選為10月5日當期的封面。EMBO為國際知名生命科學領域組織，此一成果除受到國際重視外，也是將臺灣基礎科研實力推向國際的最佳典範。

早衰症Hutchinson-Gilford progeria syndrome (HGPS)患者在嬰兒時期就開始出現發育不良、皮下脂肪變少、產生皺紋、禿頭、骨質疏鬆、心血管疾病及關節出現問題等，平均壽命只有13歲。這個疾病最早是在1886年被發現，直到2003年才知道是因LMNA基因突變所致，但是病理機轉至今仍不清楚。LMNA基因表現A型核纖層蛋白（lamin A），是構成核纖層（nuclear lamina）的主要成分之一，扮演著細胞核骨架的功能，當LMNA基因發生突變，細胞核會出現不正常的皺摺現象，甚至凹陷變形。除了早衰症之外，LMNA基因突變也與其他至少10種人類疾病有關，例如 Emery-Dreifuss肌肉萎縮症（muscular dystrophy）、擴張型心肌病變（dilated cardiomyopathy）等，這些疾病統稱為核纖層蛋白病症（laminopathy）。

陳鴻震教授研究團隊首先在早衰症病患的皮膚纖維母細胞中觀察到有較少及較短的初級纖毛，由於初級纖毛的功能就像是細胞的天線一樣，用於偵測細胞外環境的變化，進而傳遞訊息讓細胞可以調適。因此，推測初級纖毛的異常可能是導致早衰症重要的致病機轉。研究團隊進一步利用LMNA基因的缺陷小鼠進行實驗，證實在核纖層蛋白缺陷的早衰小鼠，許多器官的細胞初級纖毛都出現問題。接著團隊利用RNA干擾技術，在人類視網膜色素上皮細胞中降低核纖層蛋白的表現，也同樣造成初級纖毛的異常。在機轉的研究方面，研究團隊發現LMNA基因的缺陷，會造成細胞微絲骨架（actin cytoskeleton）的過度組裝，進而干擾初級纖毛的形成。反之，若抑制微絲骨架的組裝則可恢復初級纖毛的形成。這項發現不僅有助於了解早衰症及其他核纖層蛋白病症（laminopathy）的致病機轉，也開啟了開發治療相關疾病的嶄新研究方向。

本研究由科技部經費支持，由陳鴻震教授實驗室范嘉榕博士後研究員(第一作者) 主要負責執行；國衛院紀雅惠副研究員提供早衰症病患的皮膚纖維母細胞及早衰小鼠；陽明大學生化暨分子生物研究所游麗如教授及王琬菁副教授協助早衰小鼠的組織切片及初級纖毛的螢光染色及觀察。陳鴻震教授以優質的研發能量，集合各領域專家合作，將臺灣研究成果推向國際；更以優異的統籌規劃能力，自去年借調至科技部生科司擔任司長，未來將以領頭羊的角色繼續帶領臺灣生命科學領域朝國際頂尖學術目標邁進。

研究成果聯絡人

陳鴻震 講座教授

國立陽明大學 生化暨分子生物研究所

聯絡電話 (公): 02-2826-7123

電子郵件信箱：hcchen1029@ym.edu.tw

Press Release

October 12, 2020

Uncovering the pathogenesis of premature aging ---        

Taiwan research team found a link between progeria and cilia-deficiency, published as a cover story on EMBO Reports

Selected as the cover story of EMBO Reports on the issue of October 5th, the study led by Chair Professor Hong-Chen Chen at National Yang-Ming University in collaboration with Dr. Ya-Hui Chi at National Health Research Institutes, Taiwan, uncovers the pathogenesis of progeria may result from the malfunction of primary cilia. This finding provides with putative therapeutic strategies for progeria diseases.

The patients with Hutchinson-Gilford progeria syndrome (HGPS) appear premature symptoms in their infancy with an average life span of 13 years. The clinical phenotypes are characterized by severe growth retardation, loss of subcutaneous fat, wrinkled skin, hair loss, osteoporosis, joint stiffness, and cardiovascular diseases. Despite being described in 1886, HGPS was not attributed to mutations in the LMNA gene until 2003. However, until now the underlying pathogenesis of HGPS remains unclear. The LMNA gene produces lamin A, a major component of the nucleoskeleton called nuclear lamina. Once LMNA gene mutated, the nucleus becomes wrinkled and even undergo severe deformation. Aside from HGPS, LMAN gene mutations have been attributed to at least 10 human diseases, such as Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and so on. These diseases are collectively called laminopathies.

The research team led by Professor Hong-Chen Chen found for the first time that HGPS patients-derived skin fibroblasts show fewer and shorter primary cilia. Since the primary cilium functions like a cellular antenna that detects changes in the extracellular environments and transduces signals to the cell interior to respond those changes, it is possible that the malfunction of primary cilia may be a cause for HGPS. Therefore, the team further examined Lmna null mice, and proved that primary cilia were defective in many organs of this prematurely aged, lamin A-deficient mice. Subsequently, the researchers reduced lamin A-expression in human retinal pigment epithelial cells with a shRNA-interference technique and found this manipulation led to abnormal primary cilia in these cells. For the mechanistic study, the research team found that lamin A deficiency led to excessive assembly of the actin cytoskeleton, therefore hampering the formation of primary cilia. On the contrary, disruption of the actin filaments significantly rescued cilia formation in lamin A-deficient cells. This discovery not only provides new insights for the pathogenesis of progeria syndrome, but also shed light on new therapeutic strategies for related diseases.  

This study was supported by the Ministry of Science and Technology, Taiwan, and performed mainly by postdoctoral fellow Jia-Rong Fan (first author of this paper) in the laboratory of Professor Chen. The HGPS fibroblasts and Lmna null mice were provided by Associated Researcher Dr. Ya-Hui Chi of National Health Research Institutes, Taiwan. The immunohistochemistry of Lmna null mice and the observation of primary cilia were instructed by Professor Li-Ru You and Associated Professor Won-Jing Wang of the Institute of Biochemistry and Molecular Biology, National Yang-Ming University.

Author Information:

Hong-Chen Chen, PhD

Professor Hong-Chen Chen is Dean of School of Life Science of National Yang-Ming University at Taipei, Taiwan. He was on loan to the Department of Life Sciences of Ministry of Science and Technology in October last year.

Media Contact

Prof. Hong-Chen Chen, PhD

Institute of Biochemistry and Molecular Biology, National Yang-Ming University

TEL: 02-28267123

Email: hcchen1029@ym.edu.tw

Dr. Hui-Hsin Lee

Department of Life Sciences, Ministry of Science and Technology

TEL: 02-27377461

Email: hhlee@nstc.gov.tw