Biology subjects

Witters, P.

Publications and source records attributed to Witters, P..

2 recordsLinked to original sources

bioRxiv2026

COG5-mediated Golgi organization coordinates neural progenitor fate during human brain development

Apical radial glial cells (aRGs) are highly polarized epithelial cells that drive human cortical development through tightly regulated lineage progression. A distinctive feature of aRGs is their non-canonical Golgi organization, raising the possibility that specialized intracellular trafficking and secretory processes contribute to progenitor behaviour. However, how Golgi architecture contributes to human corticogenesis remains poorly understood. Here, we investigate this question in the context of COG5 deficiency, a rare congenital disorder of glycosylation associated with neurodevelopmental defects, using patient-derived fibroblasts and brain organoids, N-glycomics, glycolipidomics, and single-cell transcriptomics. We show that COG5 deficiency disrupts Golgi organization and impairs Golgi-to-ER retrograde trafficking. At the neurodevelopmental level, COG5-deficient organoids display altered ventricular organization and reduced basal progenitor abundance. Single-cell transcriptomic analysis reveals rewired developmental trajectories characterized by premature differentiation from apical progenitors with activation of neuronal pathways. Despite the absence of major abnormalities in plasma glycoproteins glycosylation, glycolipidomic analysis identified marked defects in glycosphingolipid maturation within patient-derived brain organoids, indicating selective impairment of neural lipid glycosylation. Transcriptomic and biochemical analyses further revealed dysregulation of developmental pathways, including reduced Notch signalling and altered localization of both cleaved Notch1 and the Golgi-associated protein ACBD3. Consistent with impaired progenitor maintenance, COG5-deficient organoids displayed altered cleavage plane orientation in apical progenitors. Together, our findings suggest a link between Golgi organization, intracellular trafficking, membrane glycosylation, and lineage progression in human neural progenitors, identifying Golgi architecture as an important regulator of apical radial glial cell biology and cortical development.

cell biology↗

bioRxiv2023

Integrating multiple omics levels using the human protein complexome as a framework, a multi-omics study of inborn errors of metabolism

Proteins organize into functional assemblies that drive diverse biological activities. Leveraging a comprehensive dataset of manually curated annotations for the human protein complexome, we investigated biological perturbations at the protein complex level. Using proteomics and transcriptomics data from fibroblasts of patients with inborn errors of metabolism (IEM) and control samples, we globally mapped information onto complex subunits to discern affected processes. Across the patient cohort (consisting of organic acidaemias, fatty acid oxidation defects and mitochondrial respiratory chain defect IEMs), mitochondrial oxidative phosphorylation emerged as the most perturbed pathway, identified through proteomics datasets. Simultaneously, metabolomics highlighted significant regulation of phospholipids in patients with Fatty Acid and Mitochondrial IEM. Moreover, proteomics analysis also revealed the dysregulation of protein complexes involved in histone (de)acetylation, a finding validated through Western Blot analysis measuring histone acetylation levels. This introduces a novel epigenetic dimension to IEM and metabolic research, suggesting avenues for further exploration. Our study demonstrates a multiomics data integration concept that maps proteomics and transcriptomics data onto model organism complexomes. This integrative approach can be extended to metabolomics and lipidomics, associating information with complexes having metabolic functions, such as enzymatic complexes. This global strategy for identifying disease-relevant perturbations offers a systems-wide perspective on molecular-level physiological and pathological changes. Such insights are crucial for devising clinical intervention strategies and prioritizing druggable pathways and complexes. The presented methodology provides a foundation for future investigations, emphasizing the importance of integrating multiomics data to comprehensively understand cellular machinery alterations and facilitate targeted therapeutic approaches.

biochemistry↗