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Convergence of TDP43 and BDNF signaling hubs in regulation of synaptic plasticity and behavior

日期: 2019-02-18
生命科学学院2019年度春季学期学术系列讲座之二
题目:Convergence of TDP43 and BDNF signaling hubs in regulation of synaptic plasticity and behavior
演讲人:Prof. Carlos Ibanez
Department of Physiology, 
Yong Loo Lin School of Medicine, NUS 
时间:2019年3月8日下午13:00-14:30
地点:金光生命科学大楼101邓佑才报告厅
主持人:饶毅教授
摘要:
Aberrant function of the RNA‐binding protein (RBP) TDP‐43 has been causally linked to multiple neurodegenerative diseases. A principal difficulty in elucidating specific pathways by which RBPs can cause disease lies in the large number of targets that can be affected by anyone of these proteins. From the point of view of network theory, RBPs can be thought of as highly connected hubs, linked to hundreds or thousands of other proteins. As many other complex systems, cellular networks follow a power-law distribution: Some nodes have a very high number of connections to other nodes (i.e., hubs), while the majority of nodes have very few. Such networks, also known as scale-free networks, are very resistant to accidental failures, but vulnerable to coordinated attacks on their principal hubs. At the two extremes, the pathophysiology of diseases caused by RBP malfunction could be explained either by the summation of the effects of all their many targets (as in a random network model) or by failure of only a small subset, those that are also network hubs themselves (as predicted by a scale-free network model). 
Our team has found that knockdown, aggregation, or disease‐associated mutation of TDP‐43 all impair intracellular sorting and activity‐dependent secretion of the neurotrophin brain‐derived neurotrophic factor (BDNF) through altered splicing of the trafficking receptor Sortilin. Adult mice lacking TDP‐43 specifically in hippocampal CA1 show memory impairment and synaptic plasticity defects that can be rescued by restoring Sortilin splicing or extracellular BDNF. Human neurons derived from patient iPSCs carrying mutated TDP‐43 also show altered Sortilin splicing and reduced levels of activity‐dependent BDNF secretion, which can be restored by correcting the mutation.
To the best of our knowledge, this study is among the first to perform rescue experiments showing that major pathophysiological consequences of TDP-43 malfunction can be reverted by restoring the correct expression of only one of its targets. BDNF, arguably the most important neurotrophin in the brain, is also a highly connected hub, controlling a myriad of processes, from axonal growth and synaptogenesis, to synapse plasticity and function. Based on these findings, we propose that major disease phenotypes caused by aberrant TDP-43 activity may be explained by the abnormal function of a handful of critical “hub” proteins, such as BDNF.
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