# Identifying pathogenic mechanisms underlying PACS1 Syndrome: implications for neural development - Research Supplement to PromoteDiversity in Health-Related Research #2

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $91,014

## Abstract

Project Summary
Neurodevelopmental disorders (NDDs) are heterogenous and usually present with complex etiology. Individuals
with these conditions present with cognitive impairment accompanied by lifelong deficits; yet remarkably little is
known about their neurological basis. Patients and their families are in desperate need for disease-modifying
therapies. However, to develop effective treatments, it is imperative to understand the dysregulation of molecular
and cellular processes leading to these conditions. PACS1 Syndrome is a NDD caused by a single R203W
substitution in the Phosphofurin Acidic Cluster Sorting 1 (PACS1) protein in over 200 patients. Moreover,
genome-wide association studies (GWAS) identified the human PACS1 locus as a susceptibility gene in severe
early-onset obesity, developmental delay, and bipolar disorder, suggesting a broader role in brain development.
PACS1 encodes a multifunctional protein which canonical cytosolic function in the secretory pathway is to direct
its cargo to the trans-Golgi Network.However, PACS1 also contains a nuclear localization signal (NLS), shuttles
to the nucleus during S phase, and, at least in highly proliferative cancer cells, regulates chromatin stability
through interaction with HDAC proteins. Despite previous studies have revealed critical PACS1 functions, the
role of PACS1 within the nucleus as well as the effect of the PACS1 R203W variant in the nervous system yet
to be determined. Thus, we have generated patient induced pluripotent stem cells (iPSCs)-derived cerebral
organoids to investigate the transcriptome of a developing patterned, three-dimensional neural structure with the
patient genetic background. By performing single cell RNA Sequencing in organoids during early development,
we generated a preliminary dataset that strongly indicate that regulates a gene expression program important
for Glutamatergic/GABAergic fate specification. Altogether, evidence regarding nuclear localization of PACS1,
in addition to our preliminary data, suggests that PACS1 has an unexplored nuclear function, possibly by
regulating gene expression in neural progenitors. Therefore, we hypothesize that PACS1 regulates
Glutamatergic/GABAergic balance through a non-canonical nuclear function that decreases as neurogenesis
proceeds. Thus, PACS1 deficits result in a shift towards GABAergic fate, generating ectopic GABAergic neurons,
subsequent Glutamatergic/GABAergic imbalance, and finally NDD phenotypes. We will test this hypothesis by
addressing whether PACS1 possesses context specific functions that differ across neural differentiation (aim1),
and deficits in PACS1 nuclear function alter Glutamatergic/GABAergic specification balance (aim2). Results from
this proposal will greatly enhance our understanding of how the PACS1 deficits affect the developing nervous
system, by uncovering a currently disregarded nuclear function. Moreover, our work will expand our knowledge
of the molecular underpinnings and conseque...

## Key facts

- **NIH application ID:** 11090151
- **Project number:** 3R01NS123163-03S1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** ALICIA DIONE GUEMEZ GAMBOA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $91,014
- **Award type:** 3
- **Project period:** 2022-08-05 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11090151

## Citation

> US National Institutes of Health, RePORTER application 11090151, Identifying pathogenic mechanisms underlying PACS1 Syndrome: implications for neural development - Research Supplement to PromoteDiversity in Health-Related Research #2 (3R01NS123163-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11090151. Licensed CC0.

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