天使症候群（Angelman Syndrome，AS）TrkB信号损伤的机制研究及靶向干预

Angelman syndrome (AS) is a severe autistic-like cognitive disorder caused by a deficient Ube3A ubiquitin ligase. Neurological deficits have been linked to dysregulation of Ca2+/calmodulin-dependent protein kinase (CaMKII) activity, resulting in impairment in long-term potentiation (LTP). Brain-derived neurotrophic factor (BDNF) is known to play a critical role in synaptic plasticity and memory. Our preliminary results found that the association of the PSD95 (postsynaptic density protein PSD95)-Gαi proteins(inhibitory heterotrimeric G proteins α subunit) with TrkB is critical for intact BDNF signaling.In AS mice, the BDNF-induced recruitment of PSD95, Gαi as well as PLCγ and Gab1 with TrkB receptors was attenuated, resulting in reduced activation of PLCγ-CaMKII and PI3K-Akt. We characterized a bridged cyclic peptide (CN2097) shown by NMR studies to uniquely bind of PSD95 with high affinity, restored BDNF-induced TrkB/PSD95/Gαi complex formation, signaling and facilitated the induction of LTP in AS mice. We propose that defective BDNF signaling is the direct reason of CaMKII abnormal, LTP loss and behavioral deficits in AS mice.The impaired association between PSD95 and Gαi might be responsible for TrkB signaling dysregulation in AS mice. The discovery that CN2097 can reinstate TrkB-signaling pathways in AS mice to facilitate LTP suggests that CN2097 might restore behavioral deficits in AS. We will also study the effects of CN2097 on postsynaptic AMPAR receptor content in the AS mice. TrkB-PSD95-Gαi signaling complex might be a beneficial drug target in treating the behavioral deficits in AS.

天使症候群(Angelman Syndrome)是由UBE3A基因缺失导致的自闭症认知障碍疾病。CaMKII活性降低是AS小鼠认知障碍主因。申请者研究发现，AS小鼠存在TrkB-PSD95(突触后致密蛋白95)耦联障碍，导致下游CaMKII活化受阻。而PSD95结合肽CN2097，恢复AS小鼠TrkB-PSD95结合、CaMKII等信号转导及LTP诱导。预实验结果揭示PSD95通过和Gαi(G蛋白抑制性α亚单位)结合，参与BDNF诱导的CaMKII的活化。而AS小鼠PSD95-Gαi不能有效结合。在本项目中，申请者利用多种生物学方法，阐明PSD95-Gαi介导TrkB信号转导的机制，解析PSD95-Gαi结合异常和AS小鼠TrkB信号损伤的关系，并观察CN2097对AS小鼠突触后膜AMPAR受体含量及学习记忆功能的影响，拟明确AS致病分子机制，为开发CN2097为AS靶向药物提供实验依据。

天使症候群（Angelman Syndrome）是由UBE3A基因缺失导致的自闭症认知障碍疾病。CaMKII活性降低及长时程增强（LTP）缺陷是AS小鼠认知障碍主因。本项目研究发现，AS小鼠存在TrkB-PSD95（突触后致密蛋白95）-Gαi耦联障碍，是AS小鼠CaMKII活性下降、LTP缺陷的直接原因，也是AS致病关键分子机制。而PSD95结合肽CN2097恢复AS小鼠TrkB-PSD95-Gαi信号转导、CaMKII活性及海马区LTP诱导，从而减轻AS模型小鼠学习记忆功能障碍。本项目初步解析了AS致病分子机制，为开发CN2097为AS靶向药物提供实验依据。