Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

Abstract

In humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in > 1–2% of patients with autism spectrum disorders—a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 can be directly ubiquitylated by UBE3A. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.

Activity-regulated E3 ubiquitin ligase TRIM47 modulates excitatory synapse development

“…Factors influencing dendritic spine structure have been shown to influence development and functions of synapse ( Sala et al, 2001 ; Pavlopoulos et al, 2011 ; Gao et al, 2017 ; Sell et al, 2021 ). We have tested the impact of TRIM47 knockdown on dendritic spine development.…”

“…We anticipate that proteasome-mediated degradation of factors influencing actin depolymerization following activity-dependent enhancement of TRIM47 could modulate the structure of the dendritic spine. The alteration of dendritic spine structure is directly correlated with the development of functional synapses and regulating synaptic potentiation during learning ( Sell et al, 2021 ). Consistent with this logical proposition, we observed that TRIM47 also acts as a negative regulator of excitatory synapse development.…”

Cntnap2-dependent molecular networks in autism spectrum disorder revealed through an integrative multi-omics analysis

“…Advances in high-throughput molecular profiling (omics) techniques have allowed researchers to understand a wide range of molecular features (e.g., mRNAs, proteins, and metabolites) and have revealed the molecular mechanism underlying NDDs [1,11,[15][16][17][18]. In addition to global gene expression profiles with the complex mixture of cells comprising bulk transcriptome samples, single-cell RNA sequencing (scRNA-seq) has enabled the investigation of gene expression profiles at the individual cell level [19].…”