Biology subjects

Schroder, A. L.

Publications and source records attributed to Schroder, A. L..

3 recordsLinked to original sources

bioRxiv2026

Molecular and functional profiling distinguishes PACS1 syndrome variant from PACS1 loss-of-function in iNeurons

PACS1 syndrome is a rare neurodevelopmental disorder caused by a recurrent de novo missense variant (p.R203W) in the PACS1 protein. However, it remains unclear whether the p.R203W variant acts through a loss-of-function or alternative mechanism. Here, we used isogenic iPSC-derived neurons (iNs) to directly compare the effects of PACS1 p.R203W to complete loss of PACS1 function. Using a combination of proteomic, biochemical and electrophysiological approaches, we identified molecular and functional phenotypes associated with each genotype. While PACS1(+/R203W) and PACS1(-/-) iNs shared phenotypic abnormalities, the overall molecular and functional consequences of the p.R203W variant were distinct from those caused by PACS1 deficiency. Notably, PACS1(+/R203W) presented with unique proteomic and kinase signaling signatures and a shift in stimulus dependent excitability. These findings demonstrate that PACS1 syndrome is not caused by a simple loss of function and instead support a non-loss-of-function mechanism. Lastly, our interactome analysis suggests that the p.R203W variant retains aspects of canonical PACS1 function while acquiring novel molecular interactions that could contribute to PACS1 syndrome pathogenesis. Altogether, these findings provide a framework for future mechanistic studies and therapeutic development in PACS1 syndrome. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/747101v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@d1522corg.highwire.dtl.DTLVardef@69e4dforg.highwire.dtl.DTLVardef@30eebcorg.highwire.dtl.DTLVardef@899b9d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Filopodia numbers impact chemotactic migration speed

Migrating cells sense and respond to external chemical and physical cues, enabling them to efficiently reach their destinations. Filopodia are slender actin-filled membrane protrusions implicated in interacting with the extracellular environment in many contexts, such as neuronal growth cone guidance and the capture of prey by immune cells and unicellular organisms. The role of filopodia in chemotactic guidance in fast-moving amoeboid cells has not been well-studied. The social amoeba Dictyostelium relies on chemotaxis for development and finding food, making it an excellent system for investigating the role of filopodia in amoeboid chemotaxis. Stimulation of amoebae with the chemoattractant cAMP activates a transient increase of filopodia formation by recruiting the filopodial myosin DdMyo7 to the cell cortex. Filopodia formation is biased towards the source of chemoattractant, yet myo7 null cells that lack filopodia exhibit normal directional migration. However, cells either lacking filopodia or having increased numbers of filopodia move more slowly than those with wildtype numbers of filopodia. Thus, while filopodia are dispensable for detection of chemical gradients by amoeboid cells, changes in filopodia number can impact their migration speed possibly due to altering cell-substrate adhesion. In briefFilopodia formation in chemotactic amoeboid cells is stimulated by chemoattractant and biased towards the gradient source. Lack of filopodia does not impair directed migration but rather reduces cell speed. Changes in filopodia number correlate with the speed of chemotactic cells suggesting a role for these extension in tuning adhesion for optimal migration. HighlightsO_LIFilopodia formation in chemotactic amoeboid cells is biased towards the source of the gradient. C_LIO_LIChemotactic Dictyostelium amoebae lacking filopodia migrate with directional persistence. C_LIO_LIMigration speed is altered by filopodia number. C_LI

cell biology↗

bioRxiv2025

PACS1 syndrome variant alters proteomic landscape of developing cortical organoids

PACS1 syndrome is a neurodevelopmental disorder (NDD) 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, autism spectrum disorder (ASD) patient-derived brain organoids have been increasingly used to identify pathogenic mechanisms and possible therapeutic targets. While most of these studies evaluate the mechanisms by which ASD-risk genes affect the transcriptome, studies considering the proteome are limited. Here, we examine 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 the PACS1 p.R203W variant accelerated the emergence of proteins related to synaptogenesis and impaired vesicle loading and recycling. The earlier presence of these proteins and their related processes could lead to defective and/or incomplete synaptic function. Key dysregulated proteins observed in PACS1(+/R203W) organoids have been associated with several neurological diseases, and many are classified as NDD-causative and ASD-risk genes. Our results highlight that proteomic analyses not only enhance our understanding of general NDD mechanisms by complementing transcriptomic studies, but could also uncover additional targets, and therefore facilitate therapy development.

neuroscience↗