Dr. Eminy H.Y. Lee, Distinguished Research Fellow at the Institute of Biomedical Sciences, Academia Sinica recently discovered that modification of a gene known to often be mutated in the autism spectrum disorder “Rett Syndrome” and other neuro-developmental disorders, can rescue the behavioral deficits of social interaction, fear memory and synaptic deficit in mice. The research team found that a post-translational modification of the MeCP2 protein could rescue the behavioral and neural deficits in Mecp2 conditional knockout mice. These results advance our understanding of Rett Syndrome and suggest new therapeutic strategies. The results were published in the February 4, 2016 issue of Nature Communications.

Rett Syndrome first became well known through a documentary film entitled “Silent Angels: The Rett Syndrome Story” narrated by actress Julia Roberts in 2000. It is a neuro-developmental disorder that is known to be closely linked to the gene MECP2. Rett Syndrome occurs in approximately 1:10,000 live female births; boys with this disorder normally do not survive. Children with Rett Syndrome usually develop normally before one and a half years old. After that, abnormal symptoms including deficits in motor function, social ability, learning and memory performance and emotional control occur that progress rapidly. Motor function deficit is often characterized by twisting hands, rubbing hands together or even placing hands into the mouth. Rett Syndrome cannot be cured. So far, drugs can only alleviate the symptoms.

The research team led by Dr. Lee recently found that the MeCP2 protein is modified by SUMO proteins – a process called SUMOylation. They found a consistent and significant decrease in MeCP2 SUMOylation in several MECP2 mutations that are often identified in Rett Syndrome patients. Using Mecp2 conditional knockout mice as a model, they found that increase in MeCP2 SUMOylation successfully rescues the behavioral and neural deficits in these mice. It also increases the level of Bdnf gene expression. BDNF protein has been demonstrated to play a very important role in enhancing learning and memory, neuroplasticity and even protection against neurodegenerative diseases.

In addition, the research team also found that insulin-like growth factor-1 (IGF-1) and corticotrophin-releasing factor (CRF) both significantly increase the level of MeCP2 SUMOylation in rat brain. Dr. Lee said, “Few reports have shown that IGF-1 has a therapeutic effect in Rett Syndrome patients. On the other hand, CRF has been demonstrated to facilitate learning and memory and increase Bdnf gene expression in the brain. Our research result can perhaps provide a novel direction for the therapeutic potential of corticosterone against Rett Syndrome in the future.”

There are three co-first authors of this paper. Dr. Derek Tai graduated from the Graduate Institute of Life Sciences, National Defense Medical Center in Taiwan 6 years ago, and now works as a postdoctoral fellow at Harvard University; Mr. Y.C. Liu is a third-year Ph.D. student enrolled in the Graduate Institute of Life Sciences, National Defense Medical Center, and Dr. W.L. Hsu is currently a postdoctoral fellow in Dr. Lee’s laboratory.

The complete list of authors is: Derek J.C. Tai, Yen C. Liu, Wei L. Hsu, Yun L. Ma, Sin J. Cheng, Shau Y. Liu, Eminy H.Y. Lee

本院生物醫學科學研究所李小媛特聘研究員日前發表最新研究成果，其研究團隊發現若增強大腦中一種名為 MeCP2 蛋白的特定後轉譯修飾作用，可挽救實驗小鼠因泛自閉症—雷特氏症 (Rett Syndrome) 所導致的社交、記憶與腦神經細胞的缺陷。這項研究成果對於瞭解雷特氏症之病因及治療方向，提供新的思考途徑，國際重要期刊《自然通訊》(Nature Communications) 於2016年2月4日刊登這篇論文。

雷特氏症是一種罕見的複雜性神經失調症，由電影女演員茱莉亞羅勃茲主述的紀錄片「沈默的天使-雷特氏症的故事」於2000年播出後，這項嚴重的身心 障礙症才逐漸為公眾知曉。雷特氏症以1萬分之一的機率好發於小女孩，男孩則早夭。病童通常在1.5歲時身心快速退化，並會出現扭手、搓手、玩手及吃手等症 狀。隨之而來會發生語言障礙、運動功能失調、社交能力變差、學習與記憶能力衰退以及情緒失調等嚴重的身心障礙症狀，有些患者甚至會發生脊椎側彎的現象。由 於嬰兒出生時是正常的，突然病變加重，對於患者與家庭的痛楚尤其深沉難言。醫學界已知雷特氏症病因與X染色體上的MECP2基因突變有關，並且可藉由基因檢測驗出，但目前無法治癒，只能依賴藥物改善。

此次，李小媛特聘研究員實驗團隊發現，在大腦的MeCP2蛋白會發生「類小泛素化」這種後轉譯修飾的現象，而這個現象可以被神經細胞的活化所誘發。研究團隊進一步證實，在雷特氏症患者最常見的幾種MECP2基 因產生突變的位點，都會呈現MeCP2類小泛素修飾明顯減少的現象。研究團隊再以基因剃除鼠為實驗對象，增加其腦中MeCP2 蛋白的類小泛素化，結果發現可以成功挽救其社交、記憶以及神經突觸可塑性的缺陷，同時會增加腦中腦源神經滋養因子的表現。腦源神經滋養因子亦早已被證實可 促進學習與記憶能力、神經可塑性，甚至減緩腦神經細胞退化。

此外，研究團隊亦證實「第一型類胰島素生長因子」和「促腎上腺皮質素釋放因子」均會顯著增加MeCP2在腦中的類小泛素修飾。李小媛特聘研究員表 示，「用前一項生長因子來治療雷特氏症是目前醫學界的最新嘗試；而後一項釋放因子則已被證實會促進大鼠的學習和記憶能力以及腦源神經滋養因子的基因表現。 這篇研究成果，或許可以提供未來治療雷特氏症新的思考方向。」

論文有三位共同第一作者，分別是美國哈佛大學博士後研究戴瑞徵博士、國防醫學院生命科學研究所博士生劉彥呈、以及本院生醫所博士後研究徐偉倫。