Biology subjects

Chidiac, R.

Publications and source records attributed to Chidiac, R..

3 recordsLinked to original sources

bioRxiv2026

TRIM9 Determines Sex-Specific β-Amyloid/Cellular Prion Protein/mGluR5 Complex Formation and Pathological Signaling in Alzheimer's Disease Mice

Biological sex is a major determinant of Alzheimers disease prevalence, yet the molecular mechanisms underlying sex-specific vulnerability remain largely unknown. Metabotropic glutamate receptor 5 (mGluR5) functions as a co-receptor for {beta}-amyloid (A{beta}42) oligomer/cellular prion protein (PrPC)-mediated pathogenic signaling in males but not females, establishing a sex-dimorphic node in {beta}-amyloid pathophysiology whose regulatory basis is undefined. Using quantitative proteomic analysis, we identify the E3 ubiquitin ligase TRIM9 as a novel mGluR5-interacting protein and a previously unrecognized sex-specific regulator of the A{beta}42/PrPC/mGluR5 complex. TRIM9 selectively associates with mGluR5 in male but not female APP/PS1 mouse brain and is required for mGluR5 to serve as a co-receptor for PrPC-dependent A{beta}42 oligomer binding. Genetic deletion of TRIM9 abolishes A{beta}42/PrPC/mGluR5 complex assembly in male APP/PS1 mice demonstrating that TRIM9 is an essential scaffold for male-specific A{beta}42 signal transduction. Loss of TRIM9 in males further reduces {beta}-amyloid pathology by restoring Akt/GSK3{beta}/ZBTB16-dependent autophagic flux, linking disruption of this complex to a defined downstream proteostatic mechanism. Together, these findings establish TRIM9 as a critical molecular determinant coupling male-specific A{beta}42/PrPC/mGluR5 complex assembly to downstream neurodegenerative signaling and {beta}-amyloid pathology. They reveal an unappreciated layer of sex-dependent complexity in mGluR5 pharmacology and identify disruption of the TRIM9/mGluR5 interaction as a potential male-specific therapeutic strategy for Alzheimers disease. Significance StatementThe molecular basis of sex differences in Alzheimers disease vulnerability remains unresolved. We show that mGluR5 functions as a male-specific co-receptor for pathogenic A{beta}42/PrPC signaling and identify the E3 ubiquitin ligase TRIM9 as the factor governing this dimorphism. TRIM9 selectively assembles the A{beta}42/PrPC/mGluR5 complex in male brain, and its genetic deletion disrupts complex formation while restoring Akt/GSK3{beta}-dependent autophagic clearance of amyloid. These findings define a sex-specific signaling axis underlying {beta}-amyloid pathogenesis and establish TRIM9 as a candidate target for sex-informed Alzheimers therapeutics.

neuroscience↗

bioRxiv2025

Notch1 induces endothelial plasticity to mediate hyaloid vessel involution

Hyaloid vascular regression is a critical developmental process essential for vitreous transparency and normal vision, yet the molecular cues orchestrating its involution remain incompletely defined. Here, we identify Notch1 as a pivotal regulator of hyaloid vessel clearance, acting independently of apoptosis to coordinate endothelial detachment, transient plasticity, and migration. Using an endothelial-specific Notch1 knockout mouse model, we demonstrate that loss of Notch1 results in persistent hyaloid vasculature characterized by excessive proliferation and stabilization of the vascular network. Mechanistically, Notch1 activation during the regression window induces endothelial-to-mesenchymal transition (EndoMT) marked by Snail1 and Slug upregulation. This transcriptional signature is accompanied by detachment of endothelial cells from the vascular tubes. In contrast, Notch1-deficient hyaloid vessels retain endothelial cells stably adherent to the vessel wall. Further analysis reveals that Wnt receptors FZD4, LRP5 and LRP6 previously implicated in hyaloid involution are transcriptionally downregulated in Notch1-deficient hyaloids, suggesting that the collaboration between these processes may occur through crosstalk between the Notch and Wnt pathways. Collectively, our findings uncover a Notch1-driven multicellular regression program that governs developmental vessel regression, redefining the molecular principles of vascular pruning. These results have broad implications for understanding vascular remodeling in both physiological and pathological contexts and may guide therapeutic strategies to modulate vascular regression in ocular disorders. One-Sentence SummaryNotch1 drives hyaloid regression through a multicellular program that defines an apoptosis-non-exclusive paradigm of vessel pruning.

cell biology↗

bioRxiv2023

A genome-wide CRISPR/Cas9 screen identifies genes that regulate the cellular uptake of α-synuclein fibrils by modulating heparan sulfate proteoglycans

Synucleinopathies are characterized by the accumulation and propagation of -synuclein (-syn) aggregates throughout the brain, leading to neuronal dysfunction and death. Understanding how these aggregates propagate from cell to cell in a prion-like fashion thus holds great therapeutic promises. Here, we focused on understanding the cellular processes involved in the entry and accumulation of pathological -syn aggregates. We used an unbiased FACS-based genome-wide CRISPR/Cas9 knockout (KO) screening to identify genes that regulate the accumulation of -syn preformed fibrils (PFFs) in cells. We identified key genes and pathways specifically implicated in -syn PFFs intracellular accumulation, including heparan sulfate proteoglycans (HSPG) biosynthesis and Golgi trafficking. We show that all confirmed hits affect heparan sulfate (HS), a post-translational modification known to act as a receptor for proteinaceous aggregates including of -syn and tau. Intriguingly, KO of SLC39A9 and C3orf58 genes, encoding respectively a Golgi-localized exporter of Zn2+, and the Golgi-localized putative kinase DIPK2A, specifically impaired the uptake of -syn PFFs uptake but not of tau oligomers, by preventing the binding of PFFs to the cell surface. Mass spectrometry-based analysis of HS chains indicated major defects in HS maturation in SLC39A9 and C3orf58 KO cells, explaining the cell surface binding deficit. Our findings now clearly establish these two genes as HSPG-modulating factors. Interestingly, C3orf58 KO human iPSC-derived microglia exhibited a strong reduction in their ability to internalize -syn PFFs. Altogether, our data establish HSPGs as major receptors for -syn PFFs binding on the cell surface and identifies new players in -syn PFFs cell surface binding and uptake.

cell biology↗