Spatial centrosome proteome of human neural cells uncovers disease-relevant heterogeneity-Reference-Cited by-同舟云学术

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

Published:2022-06-17 Issue:6599 Volume:376 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

O’Neill Adam C.¹²^ORCID,Uzbas Fatma¹²^ORCID,Antognolli Giulia¹²^ORCID,Merino Florencia¹²^ORCID,Draganova Kalina¹²^ORCID,Jäck Alex¹²^ORCID,Zhang Sirui³⁴⁵^ORCID,Pedini Giorgia⁶,Schessner Julia P.⁷^ORCID,Cramer Kimberly⁷⁸,Schepers Aloys⁹,Metzger Fabian¹⁰,Esgleas Miriam¹²,Smialowski Pawel¹²^ORCID,Guerrini Renzo¹¹^ORCID,Falk Sven¹²^ORCID,Feederle Regina⁹¹²^ORCID,Freytag Saskia¹³¹⁴,Wang Zefeng³⁴⁵^ORCID,Bahlo Melanie¹³¹⁴^ORCID,Jungmann Ralf⁷⁸^ORCID,Bagni Claudia⁶¹⁵^ORCID,Borner Georg H. H.⁷^ORCID,Robertson Stephen P.¹⁶^ORCID,Hauck Stefanie M.¹⁰^ORCID,Götz Magdalena¹²¹²^ORCID

Affiliation:

1. Physiological Genomics, Biomedical Center (BMC), Ludwig-Maximilians-Universitaet (LMU), Großhaderner Straße 9, 82152 Planegg-Martinsried, Germany.

2. Institute of Stem Cell Research, Helmholtz Center Munich, German Research Center for Environmental Health, Großhaderner Straße 9, 82152 Planegg-Martinsried, Germany.

3. CAS Key Laboratory of Computational Biology, Biomedical Big Data Center, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China.

4. University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

5. CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.

6. Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.

7. Max Planck Institute of Biochemistry, Martinsried, Germany.

8. Faculty of Physics and Center for Nanoscience, LMU, Munich, Germany.

9. Monoclonal Antibody Core Facility, Institute for Diabetes and Obesity, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany.

10. Research Unit Protein Science and Metabolomics and Proteomics Core, Helmholtz Centre Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany.

11. Neuroscience Department, Children’s Hospital Meyer–University of Florence, Florence, Italy.

12. SYNERGY, Excellence Cluster of Systems Neurology, Biomedical Center, LMU, Planegg-Martinsried, Germany.

13. Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.

14. Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.

15. Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, 1005 Lausanne, Switzerland.

16. Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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