Professor Li Min (right) and Dr Song Juxian receive a US patent for their discovery of novel autophagy regulators for treatment of neurodegenerative diseases


李敏教授 (右) 與宋聚先博士研發的新型自噬調節劑獲得一項美國專利

Synthesised curcumin analog C1 specifically binds to TFEB and promotes its nuclear translocation, and then activates autophagy and lysosome biogenesis to degrade alpha-synuclein


合成薑黃素衍生物C1特異與TFEB結合並促進其細胞核轉運,從而激活自噬與溶酶體生物合成降解α-突觸核蛋白

Date: 08 Nov 2016 (Tuesday)

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School of Chinese Medicine gains US patent for discovery of novel autophagy regulators for treatment of neurodegenerative diseases

中醫藥學院研究團隊研發新型自噬調節劑獲美國專利 有助治療神經退行性疾病

A research team led by Professor Li Min, Director of the Teaching and Research Division (CMTR), and Director of the Mr and Mrs Ko Chi Ming Centre for Parkinson’s Disease Research under the School of Chinese Medicine (SCM), recently discovered a novel autophagy regulator for the treatment of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. The research team was granted a US patent for the study, and related findings were published in the prestigious academic journal Autophagy (http://www.tandfonline.com/doi/abs/10.1080/15548627.2016.1179404). The team will explore further collaboration with a potential biotechnology company in the hope of applying such knowledge in new drug development.

Autophagy – how your body detoxifies and repairs itself – is a lysosome degradation pathway for material and energy metabolism and recycling, and plays vital roles in the growth, development and homeostasis of cells. It is essential to the functioning of human cells not only because it facilitates cell renewal and delays ageing, such a mechanism can also help protect the human body by killing bacteria and viruses when a person is infected. In addition, it can sustain the body’s functioning by recycling material and energy under adverse conditions like starvation.

Dysregulation of autophagy has been linked to the pathogenesis of a number of diseases, such as neurodegenerative diseases, cancers and diabetes. Japanese biologist Professor Yoshinori Ohsumi was awarded the 2016 Nobel Prize in Medicine for his discovery of autophagy mechanisms. Such a discovery not only helps identify the causes of diseases and develop effective medication therapies, but also implies that there is a great potential for the development of small molecule autophagy regulators in treating different human diseases..

Professor Li Min and Dr Song Juxian, Research Assistant Professor of CMTR have been actively engaged in identifying and developing novel autophagy regulators derived from Chinese medicines for the prevention and treatment of neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease. By screening a series of synthesised curcumin derivatives, they found a compound that directly binds to and activates the transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis. According to the research findings, this TFEB activator potently degrades the neurotoxic protein aggregates including the amyloid precursor protein and Tau in Alzheimer’s disease and alpha-synuclein in Parkinson’s disease in neuronal cells and animal models by inducing autophagy.

Professor Li Min said: “The development of natural autophagy regulators will further help develop new drugs for the treatment of related neurodegenerative diseases. Many researchers in the field of autophagy are interested in this compound since it directly targets TFEB without inhibiting the mammalian target of rapamycin pathway. It will not affect the normal functioning of cells during the eliminating process of the neurotoxic protein aggregates. In addition, this small molecule is orally effective and can be easily synthesised.”

中醫藥學院教學科研部主任兼高智明伉儷柏金遜症研究中心主任李敏教授率領的研究團隊,成功研發出一種新型的自噬調節劑,可望應用於治療包括阿氏海默症和柏金遜症等的神經退行性疾病。有關研究成果最近獲得一項美國專利及發表於權威學術雜誌《Autophagy》(http://www.tandfonline.com/doi/abs/10.1080/15548627.2016.1179404)。研究團隊並計劃應用此項知識技術,與生物科技公司合作研發新藥。
   
「自噬」是細胞通過溶酶體機制自我消化進行物質能量循環代謝的過程,也是調控細胞生長、發育與穩態的重要機制,有助細胞產物在合成、降解及循環中保持一個平衡狀態。它對人體細胞功能的正常運作不可或缺,除有助細胞更新、對抗衰老外,亦可在人體受感染時,消滅入侵的細菌與病毒,同時,在飢餓等惡劣的環境中,循環利用自身的物質以維持生存。

細胞自噬功能障礙與多種人類疾病的發生有密切的關係,特別是神經退行性疾病、癌症、糖尿病等。最近,日本生物學家大隅良典教授便憑藉其細胞自噬作用與相關機制的發現,獲頒發2016年諾貝爾醫學獎,除了有助了解相關疾病的成因及開發有效合適的治療藥物,也揭示了開發小分子自噬調節劑對於治療各種人類疾病具有龐大潛力。

李敏教授與教學科研部研究助理教授宋聚先博士一直致力篩選和開發源自中草藥的新型細胞自噬調節劑,通過清除病理性蛋白的聚集,以達到預防和治療包括柏金遜症和阿氏海默症在內的神經退行性疾病的目的。研究團隊通過篩選一系列的薑黃素合成衍生物,發現了其中一個化合物可以直接結合,並激活調節自噬與溶酶體生物合成的「開關」分子──轉錄因子EB (TFEB)。研究結果顯示,該TFEB激活劑在神經細胞和動物模型中,能顯著降解具有神經毒性的蛋白聚合物,包括阿氏海默症中的澱粉樣前體蛋白與Tau蛋白,以及柏金遜症中的α-突觸核蛋白。

李敏教授說:「透過研究源自中藥的自噬調節劑,可有助於研發治療神經退行性疾病的中藥新藥。很多專門研究自噬領域的專家對我們的研究表現出極大興趣,因為該化合物可直接激活TFEB而不依賴於抑制哺乳動物雷帕霉素靶標蛋白的信號通路,在清除病理性蛋白聚集的同時而不影響細胞的正常生理功能。此外,該化合物口服療效顯著,便於化學合成。」