PACS1 syndrome variant alters proteomic landscape of developing cortical organoids

PACS1 syndrome is a neurodevelopmental disorder resulting from a unique de novo p.R203W variant in Phosphofurin Acidic Cluster Sorting protein 1 (PACS1). PACS1 encodes a multifunctional sorting protein required for localizing furin to the trans -Golgi network. Although few studies have started to investigate the impact of the PACS1 p.R203W variant the mechanisms by which the variant affects neurodevelopment are still poorly understood. In recent years ASD patient-derived brain organoids have been increasingly used to identify pathogenic mechanisms and possible therapeutic targets. While most of these studies investigate the mechanisms by which ASD-risk genes affect the transcriptome studies investigating the proteome are limited. Here we investigated the effect of PACS1 p.R203W on the proteomic landscape of brain organoids using tandem mass tag (TMT) mass-spectrometry. Time series analysis between PACS1 ^(+/+) and PACS1 ^(+/R203W) organoids uncovered several proteins with dysregulated abundance or phosphorylation status including known PACS1 interactors. Although we observed low overlap between proteins with altered expression and phosphorylation the resulting dysregulated processes converged. The presence of PACS1 p.R203W variant putatively accelerated synaptogenesis and impaired vesicle loading and recycling putatively leading to defective and/or incomplete synaptic function. Finally the key dysregulated proteins observed in PACS1 ^(+/R203W) organoids were also enriched in ASD-risk genes and have been associated with other neurological diseases. Our results highlight that proteomic analyses not only enhance our understanding of general NDD mechanisms by complementing transcriptomic studies but also could uncover additional targets facilitating therapy development.