Proteomic analysis of Angelman mouse models

ABSTRACT: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of neuronal E3 ligase UBE3A. Restoring UBE3A levels is a potential disease-modifying therapy for AS and has recently entered clinical trials. There is paucity of data regarding the molecular changes downstream of UBE3A, hampering elucidation of disease therapeutics and biomarkers. Notably, UBE3A plays an important role in the nucleus but its targets have yet to be elucidated. Using proteomics, we assessed changes during postnatal cortical development in an AS mouse model. Pathway analysis revealed dysregulation of proteasomal and tRNA synthetase pathways at all postnatal brain developmental stages, while synaptic proteins were altered in adults. We confirmed pathway alterations in an adult AS rat model across multiple brain regions and highlighted region-specific differences. The top hits were altered in human AS patient neurons, supporting disease translation. UBE3A reinstatement in AS mice resulted in near complete and partial rescue of the proteome alterations in adolescence and adults respectively, supporting the notion that early restoration of UBE3A expression provides is a promising therapeutic option. We show that Transketolase (TKT), one of the most abundantly altered proteins, is a direct UBE3A substrate and is elevated in the neuronal nucleus of rat brains and human iPSC derived neurons. Taken together, our study provides a comprehensive map of UBE3A driven changes in AS across development and species, and corroborates UBE3A reinstatement as a viable therapeutic option.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Nikhil Janak Pandya  

PROVIDER: MSV000087972 | MassIVE | Thu Aug 12 00:09:00 BST 2021

REPOSITORIES: MassIVE