Abstract
Author SummaryAngelman syndrome (AS) is a debilitating neurological disorder caused by a dysfunctional Ube3A gene. Most children with AS exhibit developmental delay, movement disorders, speech impairment, and often autistic features. The Ube3A enzyme normally regulates the degradation of the synaptic protein Arc, and in its absence the resulting elevated levels of Arc weaken synaptic contacts, making it difficult to generate long-term potentiation (LTP) and to process and store memory. In this study, we show that increased levels of Arc disrupt brain-derived neurotrophic factor (BDNF) signaling through the TrkB receptor (which is important for both the induction and maintenance of LTP). We find that the association of the postsynaptic density protein PSD-95 with TrkB is critical for intact BDNF signaling, and that the high levels of Arc in AS interfere with BDNF-induced recruitment of postsynaptic density protein-95 (PSD-95) and other effectors to TrkB. By disrupting the interaction between Arc and PSD-95 with the novel cyclic peptidomimetic compound CN2097, we were able to restore BDNF signaling and improve the induction of LTP in a mouse model of AS. We propose that the disruption of TrkB receptor signaling at synapses contributes to the cognitive dysfunction that occurs in Angelman syndrome.
Highlights
Angelman syndrome (AS) is a severe cognitive disorder caused by loss of expression of the maternally inherited allele of the Ube3A ubiquitin ligase gene [1,2]
We show that increased levels of Arc disrupt brain-derived neurotrophic factor (BDNF) signaling through the TrkB receptor
We find that the association of the postsynaptic density protein PSD-95 with TrkB is critical for intact BDNF signaling, and that the high levels of Arc in AS interfere with BDNF-induced recruitment of postsynaptic density protein-95 (PSD-95) and other effectors to TrkB
Summary
Angelman syndrome (AS) is a severe cognitive disorder caused by loss of expression of the maternally inherited allele of the Ube3A ubiquitin ligase gene [1,2]. Ube3A ubiquitinates and degrades the immediate-early gene Arc (activity-regulated cytoskeletal-associated protein) [10], whose expression is required for LTP consolidation [11,12] and experience-dependent plasticity [13,14,15]. Arc has been reported to associate with postsynaptic density protein-95 (PSD-95) [19], the prototypical PDZ (PSD-95/Discs large/zona occludens-1) postsynaptic protein [20,21], known to play a key role in the endocytosis of synaptic AMPARs [22,23,24] and to regulate AMPAR incorporation at synapses [25,26,27,28]. The PDZ domains of PSD-95 bind the cytoplasmic tails of select NMDA and Kainate
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