PACS1 syndrome variant alters the proteomic landscape of developing cortical organoids.
- 1Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
- 2Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Abstract
Patient-derived brain organoids have been used to model NDDs and identify pathogenic mechanisms. While most studies have evaluated the mechanisms by which NDD variants affect the transcriptome, studies examining the proteome remain limited. Here, we examined the effect of the PACS1 p.R203W variant, which causes PACS1 syndrome, on the proteomic landscape of brain organoids and compared the results with a transcriptomic dataset. Although we observed limited overlap between transcripts and proteins, most dysregulated processes converged. The proteomic data not only reinforced the importance of these developmental processes in p.R203W pathogenesis but also revealed dysregulated pathways not identified in the transcriptomic analysis. Key dysregulated transcripts and proteins in PACS1(+/R203W) organoids were classified as NDD-causative and ASD-risk genes. Our results highlight the potential of proteomics to complement transcriptomic studies by providing deeper insight into the mechanisms underlying NDDs while revealing additional therapeutic targets that may not be identifiable through transcriptomics alone.
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BibTeX
@article{gomezmaqueo2026pacs1,
title = {{PACS1 syndrome variant alters the proteomic landscape of developing cortical organoids.}},
author = {Ximena Gomez-Maqueo and Lauren E Rylaarsdam and Ashley Woo and Annika L Schroder and Jennifer Rakotomamonjy and Clare L Bossert and Tess A Smith and Shelby Ruiz and Jordan Gilardi and Lambertus Klei and Bernie Devlin and Matthew L MacDonald and Alicia Guemez-Gamboa},
journal = {IScience},
year = {2026},
month = sep,
doi = {10.1016/j.isci.2026.117566},
url = {https://europepmc.org/article/MED/42835086},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - PACS1 syndrome variant alters the proteomic landscape of developing cortical organoids.
AU - Ximena Gomez-Maqueo
AU - Lauren E Rylaarsdam
AU - Ashley Woo
AU - Annika L Schroder
AU - Jennifer Rakotomamonjy
AU - Clare L Bossert
AU - Tess A Smith
AU - Shelby Ruiz
AU - Jordan Gilardi
AU - Lambertus Klei
AU - Bernie Devlin
AU - Matthew L MacDonald
AU - Alicia Guemez-Gamboa
PY - 2026
DA - 2026/09/24
JO - IScience
DO - 10.1016/j.isci.2026.117566
UR - https://europepmc.org/article/MED/42835086
AB - Patient-derived brain organoids have been used to model NDDs and identify pathogenic mechanisms. While most studies have evaluated the mechanisms by which NDD variants affect the transcriptome, studies examining the proteome remain limited. Here, we examined the effect of the PACS1 p.R203W variant, which causes PACS1 syndrome, on the proteomic landscape of brain organoids and compared the results with a transcriptomic dataset. Although we observed limited overlap between transcripts and proteins, most dysregulated processes converged. The proteomic data not only reinforced the importance of these developmental processes in p.R203W pathogenesis but also revealed dysregulated pathways not identified in the transcriptomic analysis. Key dysregulated transcripts and proteins in PACS1(+/R203W) organoids were classified as NDD-causative and ASD-risk genes. Our results highlight the potential of proteomics to complement transcriptomic studies by providing deeper insight into the mechanisms underlying NDDs while revealing additional therapeutic targets that may not be identifiable through transcriptomics alone.
SN - 2589-0042
ER -