The centrosome provides an intracellular anchor for the cytoskeleton, regulating cell division, cell migration, and cilia formation. We used spatial proteomics to elucidate protein interaction networks at the centrosome of human induced pluripotent stem cell-derived neural stem cells (NSCs) and neurons. Centrosome-associated proteins were largely cell type-specific, with protein hubs involved in RNA dynamics. Analysis of neurodevelopmental disease cohorts identified a significant overrepresentation of NSC centrosome proteins with variants in patients with periventricular heterotopia (PH). Expressing the PH-associated mutant pre-mRNA-processing factor 6 (PRPF6) reproduced the periventricular misplacement in the developing mouse brain, highlighting missplicing of transcripts of a microtubule-associated kinase with centrosomal location as essential for the phenotype. Collectively, cell type-specific centrosome interactomes explain how genetic variants in ubiquitous proteins may convey brain-specific phenotypes.

O'Neill, A.c., Uzbas, F., Antognolli, G., Merino, F., Draganova, K., Jäck, A., et al. (2022). Spatial centrosome proteome of human neural cells uncovers disease-relevant heterogeneity. SCIENCE, 376(6599), 1-11 [10.1126/science.abf9088].

Spatial centrosome proteome of human neural cells uncovers disease-relevant heterogeneity

Pedini, Giorgia;Bagni, Claudia;
2022-06-17

Abstract

The centrosome provides an intracellular anchor for the cytoskeleton, regulating cell division, cell migration, and cilia formation. We used spatial proteomics to elucidate protein interaction networks at the centrosome of human induced pluripotent stem cell-derived neural stem cells (NSCs) and neurons. Centrosome-associated proteins were largely cell type-specific, with protein hubs involved in RNA dynamics. Analysis of neurodevelopmental disease cohorts identified a significant overrepresentation of NSC centrosome proteins with variants in patients with periventricular heterotopia (PH). Expressing the PH-associated mutant pre-mRNA-processing factor 6 (PRPF6) reproduced the periventricular misplacement in the developing mouse brain, highlighting missplicing of transcripts of a microtubule-associated kinase with centrosomal location as essential for the phenotype. Collectively, cell type-specific centrosome interactomes explain how genetic variants in ubiquitous proteins may convey brain-specific phenotypes.
17-giu-2022
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/13 - BIOLOGIA APPLICATA
English
O'Neill, A.c., Uzbas, F., Antognolli, G., Merino, F., Draganova, K., Jäck, A., et al. (2022). Spatial centrosome proteome of human neural cells uncovers disease-relevant heterogeneity. SCIENCE, 376(6599), 1-11 [10.1126/science.abf9088].
O'Neill, Ac; Uzbas, F; Antognolli, G; Merino, F; Draganova, K; Jäck, A; Zhang, S; Pedini, G; Schessner, Jp; Cramer, K; Schepers, A; Metzger, F; Esgle...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/317019
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