Seminar：From understanding neural plasticity to drug discovery for neurodegenerative diseases
Title: From understanding neural plasticity to drug discovery for neurodegenerative diseases
Speaker: Professor Nancy Y. Ip, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China
Time: 21st Oct, 2013 (Monday), 10:00
Place: Room205, Administration Building
Host: Professor Shuming Duan
Introduction
Neurodegenerative diseases, such as Alzheimer’s disease, are emerging to become a major health burden in societies with a large aging population. Increasing evidence suggests that dysfunction in neural communication plays a key role in the onset and progression of neurodegenerative diseases.Neurons in the brain communicate with each other through chemical transmission at specialized structures known as synapses. Experience-dependent modification of synaptic transmission or synaptic plasticity forms the cellular basis of cognitive functions such as learning and memory. Loss of synapsesor impaired synaptic plasticity hasbeen observed at early stages of Alzheimer’s disease before extensive neuronal death. Thus, explicating the molecular mechanisms involved in the establishment and remodeling of synapsesis pivotal for identifying new drug targets and developing neurotherapeutic agents.
Synaptic remodeling is believed to be precisely regulated by the co-ordinated activation of diverse cell surface receptors. My laboratory is interested in understanding howneurons transduce signals from these cell surface receptors to regulatesynapse function and plasticityof the adult brain under normal and diseased conditions.We have recently identified distinct receptor-mediated signaling pathways that can positively or negatively regulate neurotransmission, thereby differentially promote the strengthening and weakening of existing synapses. For example, the receptor tyrosine kinase TrkB binds to the growth factor BDNF and modulates structural changes of the synapse during memory formation. Similarly, the G-protein-coupled receptor melanocortin-4 receptor (MC4R), the cognate receptor of the neuropeptide α-MSH, enhances hippocampal synaptic plasticity through the regulation of synapse morphology and the trafficking of neurotransmitter receptors. On the other hand, another receptor tyrosine kinase, EphA4, is a major negative regulator of neurotransmission. Activation of EphA4 attenuates synaptic transmission by promoting the degradation of neurotransmitter receptors and the loss of synaptic contacts. We further demonstrate that EphA4 is important in mediating the synaptic dysfunctions during the progression of Alzheimer’s disease, suggesting that this receptor is a promising target for developing new treatments for this devastating neurodegenerative disease.
In our attempt to translate our discoveries from basic research to the development of neurotherapeutic agents, we have leveraged our research strengths in molecular neuroscience and Chinese medicine (CM) to establish a focused drug discovery program in search of new drug leads, including those that can regulate synaptic activity.Our major objective is to utilize a systematic knowledge-based approach to screen for neuroactive lead compounds from CM. Through discovery ofnew molecular targets in neurodegenerative diseases, we have screened for potential modulators of these targets using specific bioassay platforms or structure-based molecular docking approach. Natural compounds from CM that display high binding affinity to specific molecular targets have been identified and characterized. This drug discovery strategy has proven to be a very effective approach in identifying potential drug candidates, some of which are currently at various stages of pre-clinical development for neurological disorders.
