技部新聞稿
顫抖症的成因找到了
日期：109年2月18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
您拿碗、拿杯子手會抖嗎？拿筷子想要好好夾食物，結果手抖得更厲害嗎？這正是「原發性顫抖症」的主要症狀。
原發性顫抖症，這個常見的動作障礙疾病，是以活動中的手抖、頭抖或聲音抖等顫抖症狀來表現。在成年人中，有超過4%的人有此一疾病，在老年人口中更佔了近20%。可惜的是，如此常見的疾病，在基因及血液診斷發達的時代，仍找不到致病機轉。病因不明，也是此一病徵被成為“原發性”顫抖症的原因。在臨床治療上，目前顫抖症的藥物治療不佳，比較有效的治療必須以手術破壞大腦深處的細胞，或在腦部埋入電刺激器來治療。但即使手術治療一開始有效佳的療效，在數年之後療效也會慢慢減弱。
在科技部「以疾病為導向之腦與心智科學專案研究計畫」(106-108)及「臺灣腦科技及國際躍升計畫」(108-110)對跨國、跨領域整合性研究的支持下，臺大醫學院的潘明楷助理教授兼任醫師與美國哥倫比亞大學醫學中心的郭昇翰醫師成立跨國合作團隊，找出第一個顫抖症的致病機轉。研究發現，顫抖症病患的小腦細胞，其中控制神經連結的GluRδ2蛋白會減少，導致小腦神經纖維的過度增生，使得小腦細胞產生過強的連結，造成小腦神經的過度共振，進而產生顫抖症狀。除上述機轉之外，小腦神經的共振異常，更可成為檢測原發性顫抖症的第一個生物標記，幫助顫抖症的臨床診斷及藥物開發。潘醫師與郭醫師結合哥大的完整腦庫、病理專長，及臺大的活體動物研究及先進光電技術，先在顫抖症病患腦庫的病理分析中，觀察到顫抖症特有的小腦結構及分子變化，並依此建立動物模式，以先進的活體小鼠小腦電生理及光遺傳學技術進行神經機轉的研究，找出顫抖症的神經迴路及共振異常，並進一步開發小腦腦波的臨床電生理新技術，真正在顫抖症病患上確認小腦共振異常。此研究成果，今年初發表在國際頂尖轉譯醫學期刊 Science Translational Medicine 12(526), 2020 (IF:17.2)。已有美國及日本等數個國際藥廠，與此團隊合作，利用新開發的動物模式及小腦腦波新技術，進行顫抖症的藥物開發及試驗，並針於GluRδ2蛋白設計基因治療方法，逆轉GluRδ2蛋白的缺損。
此一跨國團隊的研究方向及合作模式，獲國際重視，受美國國家衛生研究院補助。哥倫比亞大學並成立新的中心(Initiative of Columbia Ataxia and Tremor , iCAT)(註一)，由郭醫師為中心主任，推動相關研究。潘醫師亦成為世界動作障礙學會(Tremor Study Group)的臺灣代表(註二)，共同制定顫抖症相關的國際診斷治療官方準則。此外，兩位醫師更成為國際頂尖期刊 British Medical Journal線上醫學資料庫BMJ Best Practice顫抖症章節的長期特約作者(註三)。
近年科技部積極推動上述神經科學及科技的創新專案計畫，促進臺灣生醫資源和科技優勢的跨校資源整合。以臺大分子影像中心為例，校內結合物理系朱士維教授、醫工所林頌然老師的先進光學技術及心理系賴文崧教授的動物行為回饋系統，加上陽明大學神經科學研究所連正章所長及清華大學江安世院士的支持，進一步整合「光纖光子計量術」、「組織透明化」及「超解析影像」等尖端技術，期待未來以臺灣的科技優勢協助生物醫學研究，嘉惠病患。
註二： https://www.movementdisorders.org/MDS/About/Study-Groups/Tremor-Study-Group.htm
註三：
https://bestpractice.bmj.com/topics/en-gb/1089
研究成果聯絡人
潘明楷 助理教授
國立臺灣大學醫學院藥理學科暨研究所
國立臺灣大學分子影像中心
國立臺灣大學神經生物與認知科學中心
臺大醫院雲林分院兼任主治醫師
聯絡電話(公)：02-23123456 #88316
電子郵件信箱：emorymkpan@ntu.edu.tw
Press Release
Feb. 18, 2020
Finding the mechanism of Essential tremor
What is essential tremor? Why it is important?
Do you have shaking hands when using spoons, holding a bow or signing a document? Do you feel frustrated that the more you try to control the move, the worse the shakes will be? Such symptom is called action tremor and is the core feature of essential tremor (ET), the most common movement disorder that affects 4% of adults, up to 20% of elderly population and is 5 times more prevalent than Parkinson’s disease.
While ET is such a common disorder, the mechanism of ET remains largely unknown. Clinically, only two ET medications are FDA approved with the responsive rates less than 50%. Surgical treatment, such as thalamic deep brain stimulation or thalamotomy, could have better initial outcomes, but the therapeutic effects may gradually wear off and we don’t know why.
The discovery of ET mechanism and clinical biomarker
Based on the support of Ministry of Science and Technology in Taiwan (MOST), we established a long-term collaboration with Columbia University Medical Center (CUMC) in tremor research. By incorporating the advantage of human pathology (CUMC) and optical-electrical technology in live animal/human researches (National Taiwan University, NTU), we found a mechanism of ET and developed a new technique (cerebellar electroencephalography, or cerebellar EEG) and a related clinical biomarker (abnormal cerebellar oscillations) for ET.
Starting with human pathology, we observed that the cerebellum, the “small brain”, of ET patient develops too many cerebellar climbing fibers. The overgrowth of cerebellar fibers is associated with the loss of a cerebellar protein called GluRδ2, whose function is to stabilize the synapses between the fibers and the neurons and therefore control the fiber growth. These findings triggered us to identify a GluRδ2-deficient mouse model, which also develops climbing fiber overgrowth and ET-like action tremor. With the animal model, we can apply state-of-the-art optogenetic technology, which can use light to control the activities of brain cells with the precision to millisecond scale, while recording the corresponding neuronal activities and mouse behavioral changes in real-time. We found that the loss of GluRδ2 protein leads to the overgrowth of cerebellar climbing fibers, whose activities cause too much synchronization and oscillations of cerebellar neurons and therefore generate tremor. The mouse findings drove us to develop a new technique called cerebellar EEG, which can record human cerebellar electric activities non-invasively. We found that excessive cerebellar oscillations also exist in ET patients and can serve as a biomarker in ET.
In summary, we found a pathophysiology of ET, with mutually referenced mouse and human evidence spanning molecular (GluRδ2 deficiency), structural (cerebellar fiber overgrowth), physiological (excessive cerebellar oscillations) and behavioral (action tremor) levels. More importantly, the discovery of an ET mechanism and the corresponding clinical biomarker by novel cerebellar EEG tehcnology could significantly benefit clinical diagnosis and guide the new drug development in future works. The study results have been published in Science Translational Medicine 12(526), 2020.
Technology integration facilitates neuroscience research in Taiwan
Supported by brain science projects from MOST, Taiwan is developing multi-disciplinary and fully integrative teams in the field of neuroscience researches. In fact, this study is an outcome of the integrative facility established in Molecular Imaging Center, NTU. The facility incorporates multiple electro-optic technologies from different Universities, including optogenetics with simultaneous electrophysiology (Ming-Kai Pan, NTU college of medicine), artificial-intelligent (AI)-based behavioral tracking system (Wen-Sung Lai, NTU), in-vivo multi-photon imaging of live behaving animals (Sung-Jan Lin & Shi-Wei Chu, NTU), fiber photometry (Cheng-Chang Lien, National Yang-Ming University), tissue-clearing and super-resolution imaging (Ann-Shyn Chiang, National Tsing Hua University). Moreover, the animal-to-human translation and advances in cerebellar EEG are held in National Taiwan University Hospital, Yun-Lin Branch. These integrative works provides unbiased, multi-dimensional approaches by state-of-the-art electro-optic technologies with tightly linked pipeline of animal-to-human translation. By incorporating the strong support and advances of electrical engineering and optical technologies in Taiwan, we could use these technologies to push the neuroscience research forward and help improving human health in neurological diseases.
Author Information:
Ming-Kai Pan, M.D., Ph.D.
The author is currently an assistant professor, Institute of Pharmacology, National Taiwan University College of Medicine. Dr. Pan is also affiliated to Molecular Imaging Center (MIC) and Neurobiology and Cognitive Science Center (NCSC) in National Taiwan University, and is an attending physician of National Taiwan University Hospital, Yun-Lin Branch. Internationally, he is also a committee member of Tremor Study Group (TSG) in International Parkinson’s Disease and Movement Disorder Society (MDS).
Media Contact
Dr. Ming-Kai Pan
Institute of Pharmacology, National Taiwan University College of Medicine
TEL: 02-23123465 ext.88316
Email：emorypan@gmail.com
Dr. Hui-Hsin Lee
Department of Life Sciences, Ministry of Science and Technology
TEL: 02-27377461
Email: hhlee@nstc.gov.tw
