Patient derived model of UBA5-associated encephalopathy identifies defects in neurodevelopment and highlights potential therapies [scRNA-seq]

UBA5 encodes for the E1 enzyme of the UFMylation cascade, which plays an essential role in ER homeostasis. The clinical phenotypes of UBA5-associated encephalopathy includes developmental delays, epilepsy and intellectual disability. To date, there is no humanized neuronal model to study the cellular and molecular consequences of UBA5 pathogenic variants. We developed and characterized patient-derived cortical organoid cultures and identified defects in GABAergic interneuron development. We demonstrated aberrant neuronal firing and microcephaly phenotypes in affected organoids. Mechanistically, we show that ER homeostasis is perturbed along with exacerbated unfolded protein response pathway in cells expressing UBA5 pathogenic variants. We also assessed two gene expression modalities that augmented UBA5 expression to rescue aberrant molecular and cellular phenotypes. Our study provides a novel humanized model that allows further investigations of UBA5 variants in the brain and highlights novel systemic approaches to alleviate cellular aberrations for this rare, developmental disorder. Overall design: scRNA-seq samples from proband cortical organoids compared to those from control cortical organoids of parent