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

Abstract (Expand)

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.

Authors: Adam C O'Neill, Fatma Uzbas, Giulia Antognolli, Florencia Merino, Kalina Draganova, Alex Jäck, Sirui Zhang, Giorgia Pedini, Julia P Schessner, Kimberly Cramer, Aloys Schepers, Fabian Metzger, Miriam Esgleas, Pawel Smialowski, Renzo Guerrini, Sven Falk, Regina Feederle, Saskia Freytag, Zefeng Wang, Melanie Bahlo, Ralf Jungmann, Claudia Bagni, Georg H H Borner, Stephen P Robertson, Stefanie M Hauck, Magdalena Götz

Date Published: 17th Jun 2022

Publication Type: Journal

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