New Drug Discovery for Aging-associated Neurodegenerative Disorders-Parkinson's Disease

Aging-associated neurodegenerative disorders including Parkinson’s disease (PD) have provoked a huge socioeconomic and healthcare burden globally. PD typically affects the elderly, with 1% prevalence among people over the age of 60, and caused about 117,400 deaths globally in 2015. Clinically, PD is mainly manifested by motor dysfunction, such as tremor and slow movement, which is initiated by the progressive loss of dopamine-secreting neurons in an area of the midbrain called the substantia nigra (SN). The main pathological marker Lewy bodies (LBs) are abnormal protein aggregates composed of alpha-synuclein. Unfortunately, current medications for PD can only relieve symptoms by replenishing dopamine. As the disease deteriorates, these treatments become less effective while producing severe side effects. Therefore, there is an urgent need for developing new therapeutic agents to slow down the neurodegenerative process.

Impairment of autophagy, a highly conserved cellular homeostatic process for the bulk degradation of long-lived proteins, protein aggregates, and cellular organelles, has been proved as a key pathogenic factor in PD. Mice deficient for autophagy genes develop PD-like symptoms, while upregulation of such genes ameliorates the disease course. Accordingly, enhancing autophagy holds a promising alternative for PD treatment. In previous studies, we worked on targeting the autophagy pathway with small molecules derived from Traditional Chinese Medicines to potentially discover new anti-PD drugs. Several candidates, such as the curcumin analog C1 and celastrol, were identified as activators of transcription factor EB (TFEB), a master regulator of autophagy, and showed good activity in PD models.

Based on preliminary data, we propose to advance the drug development process by fulfilling the following aims:
 

1. To examine the efficacy and mechanism of actions of autophagy enhancers in degrading the alpha-synuclein aggregates, preventing neuronal loss and motor function deficit in PD animal models;
2. To determine the roles of inflammation and immune responses in PD animal models regulated by autophagy enhancers;
3. To optimise the anti-PD activities of autophagy enhancers by structural modification of lead compounds; and
4. To optimise the anti-PD activities of autophagy enhancers by developing brain-targeting drug-delivery systems.

Through the four approaches of understanding the disease and its impact on health, discovering new therapeutic agents and developing new technology on macromolecular machines for delivery and treatment, we will make a leap forward in the treatment of neurodegenerative disorders such as PD in the elderly population.

New Drug Discovery for Aging-associated Neurodegenerative Disorders-Parkinson's Disease

Research Output
 

1. Cai CZ, Yang C, Zhuang XX, Yuan NN, Wu MY, Tan JQ, Song JX, Cheung KH, Su H, Wang YT, Tang BS, Behrends C, Durairajan SSK, Yue Z, Li M, Lu JH. NRBF2 is a RAB7 effector required for autophagosome maturation and mediates the association of APP-CTFs with active form of RAB7 for degradation. Autophagy. 2020:1-19. https://www.tandfonline.com/doi/full/10.1080/15548627.2020.1760623
2. Wang ZY, Yang C, Liu J, Chun-Kit Tong B, Zhu Z, Malampati S, Gopalkrishnashetty Sreenivasmurthy S, Cheung KH, Iyaswamy A, Su C, Lu J, Song J, Li M. A Curcumin Derivative Activates TFEB and Protects Against Parkinsonian Neurotoxicity in Vitro. Int J Mol Sci. 2020;21(4). https://www.mdpi.com/1422-0067/21/4/1515
3. Malampati S, Song JX, Chun-Kit Tong B, Nalluri A, Yang CB, Wang Z, Gopalkrishnashetty Sreenivasmurthy S, Zhu Z, Liu J, Su C, Krishnamoorthi S, Iyaswamy A, Cheung KH, Lu JH, Li M. Targeting Aggrephagy for the Treatment of Alzheimer's Disease. Cells. 2020;9(2). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072705/
4. Liu J, Liu C, Zhang J, Zhang Y, Liu K, Song JX, Sreenivasmurthy SG, Wang Z, Shi Y, Chu C, Zhang Y, Wu C, Deng X, Liu X, Song J, Zhuang R, Huang S, Zhang P, Li M, Wen L, Zhang YW, Liu G. A Self-Assembled α-Synuclein Nanoscavenger for Parkinson's Disease. ACS Nano. 2020;14(2):1533-49. https://pubs.acs.org/doi/abs/10.1021/acsnano.9b06453
5. Wu MY, Liu L, Wang EJ, Xiao HT, Cai CZ, Wang J, Su H, Wang Y, Tan J, Zhang Z, Wang J, Yao M, Ouyang DF, Yue Z, Li M, Chen Y, Bian ZX, Lu JH. PI3KC3 subunit NRBF2 is required for apoptotic cell clearance to restrict intestinal inflammation. Autophagy. 2020. https://www.tandfonline.com/doi/abs/10.1080/15548627.2020.1741332?journalCode=kaup20
6. Song JX, Malampati S, Zeng Y, Durairajan SSK, Yang CB, Tong BC, Iyaswamy A, Shang WB, Sreenivasmurthy SG, Zhu Z, Cheung KH, Lu JH, Tang C, Xu N, Li M. A small molecule transcription factor EB activator ameliorates beta-amyloid precursor protein and Tau pathology in Alzheimer's disease models. Aging Cell. 2019:e13069. https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13069
7. Wang ZY, Sreenivasmurthy SG, Song JX, Liu JY, Li M. Strategies for brain-targeting liposomal delivery of small hydrophobic molecules in the treatment of neurodegenerative diseases. Drug Discov Today. 2019;24(2):595-605. https://www.sciencedirect.com/science/article/pii/S1359644618301612
8. Tong BC, Wu AJ, Li M, Cheung KH. Calcium signaling in Alzheimer's disease & therapies. Biochim Biophys Acta Mol Cell Res. 2018;1865(11 Pt B):1745-60. https://www.sciencedirect.com/science/article/pii/S0167488918302088
9. Wang T, Cai ZW, Chen YY, Lee WK, Kwan CS, Li Min, Chan Albert S C, Chen ZF, Cheung Allen KL, Leung K. MALDI-MS Imaging Analysis of Non-inflammatory Type III Rotaxane Dendrimers. Journal of the American Society for Mass Spectrometry. (Under revision)

Awards

1. Dr. Benjamin C.K. Tong won the “Best Poster Award” for his poster presentation at the 9th International Symposium on Autophagy 3 - 7 November 2019, Taipei, Taiwan.
2. Mr. Aston Jiaxi WU (PhD candidate) won the "Best Poster Presentation Award" in the 2nd China Conference on Autophagy, 10 - 12 October 2019, Hangzhou, Zhejing, China.
3. Dr. Ashok Iyaswamy won the "Young Investigator Award" at the International Alzheimer’s Disease Conference 2019, 31 May - 1 June 2019, Hong Kong.
4. Dr. Benjamin C.K. Tong from CPDR won the "Young Investigator Award" at the 14th International Symposium on Healthy Aging, 16 - 17 March 2019, Hong Kong.
5. Mr. Sravan Gopalkrishnashetty Sreenivasmurthy (PhD Candidate) won the “Third Place Presentation Award” at the 2018 Postgraduate Symposium on Chinese Medicinal Sciences held on 29th October 2018 in University of Macau.

Patents

1. Min Li, Iyaswamy A, Durairajan SSK, Krishnamoorthi S, Huang Z, Sreenivasamurthy GS. Uses and development of NeuroDefend for treating neurodegenerative diseases, US patent No. US2019/0282646 A1 https://patents.google.com/patent/US20190282646A1/en?oq=US2019%2f0282646+A1
2. Min Li, Juxian SONG, Yu Zeng, Liangfeng LIU. MTOR-independent activator of TFEB for autophagy enhancement and uses thereof, US patent No. US9351946 B2
   https://patents.google.com/patent/US9351946B2/
3. Min Li, Juxian SONG, Chuanbin YANG, Yu Zeng, Sandeep MALAMPATI, Hongjie ZHANG. MTOR-independent activator of TFEB for autophagy enhancement and uses thereof, US patent No. US9540299 B2 https://patents.google.com/patent/US9540299B2/en?oq=US9540299+B2
4. Min Li, Siva Sundara Kumar DURAIRAJAN, Lei Lei CHEN, Liang Feng LIU, Ju Xian SONG. Composition comprising Rhizoma coptidis, Cortex phellodendri and Fructus gardeniae and for treating neurodegenerative diseases, US patent No. US9375457 B2
   https://patents.google.com/patent/US9375457B2/en?oq=US9375457+B2
5. Min Li, Liang Feng LIU, Ju Xian SONG, Hong Jie ZHANG. Synthesis of autophagy inducing compound and the uses thereof. US patent No.US9604987
   https://patents.google.com/patent/US9604987B2/en?oq=US9604987