BraInMap Elucidates the Macromolecular Connectivity Landscape of Mammalian Brain

Reza Pourhaghighi; Peter E A Ash; Sadhna Phanse; Florian Goebels; Lucas Z M Hu; Siwei Chen; Yingying Zhang; Shayne D Wierbowski; Samantha Boudeau; Mohamed T Moutaoufik; Ramy H Malty; Edyta Malolepsza; Kalliopi Tsafou; Aparna Nathan; Graham Cromar; Hongbo Guo; Ali Al Abdullatif; Daniel J Apicco; Lindsay A Becker; Aaron D Gitler; Stefan M Pulst; Ahmed Youssef; Ryan Hekman; Pierre C Havugimana; Carl A White; Benjamin C Blum; Antonia Ratti; Camron D Bryant; John Parkinson; Kasper Lage; Mohan Babu; Haiyuan Yu; Gary D Bader; Benjamin Wolozin; Andrew Emili

doi:10.1016/j.cels.2020.03.003

BraInMap Elucidates the Macromolecular Connectivity Landscape of Mammalian Brain

Cell Syst. 2020 Apr 22;10(4):333-350.e14. doi: 10.1016/j.cels.2020.03.003.

Authors

Reza Pourhaghighi¹, Peter E A Ash², Sadhna Phanse³, Florian Goebels¹, Lucas Z M Hu¹, Siwei Chen⁴, Yingying Zhang⁴, Shayne D Wierbowski⁴, Samantha Boudeau², Mohamed T Moutaoufik⁵, Ramy H Malty⁵, Edyta Malolepsza⁶, Kalliopi Tsafou⁶, Aparna Nathan⁶, Graham Cromar⁷, Hongbo Guo¹, Ali Al Abdullatif², Daniel J Apicco², Lindsay A Becker⁸, Aaron D Gitler⁸, Stefan M Pulst⁹, Ahmed Youssef¹⁰, Ryan Hekman¹¹, Pierre C Havugimana¹², Carl A White¹¹, Benjamin C Blum¹¹, Antonia Ratti¹³, Camron D Bryant², John Parkinson⁷, Kasper Lage⁶, Mohan Babu⁵, Haiyuan Yu⁴, Gary D Bader¹, Benjamin Wolozin¹⁴, Andrew Emili¹⁵

Affiliations

¹ Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.
² Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
³ Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Department of Biochemistry, University of Regina, Regina, SK, Canada; Center for Network Systems Biology, Boston University, Boston, MA, USA.
⁴ Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY, USA.
⁵ Department of Biochemistry, University of Regina, Regina, SK, Canada.
⁶ Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard University, Boston, MA, USA.
⁷ Program in Molecular Medicine, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.
⁸ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Department of Neurology, University of Utah, Salt Lake City, UT, USA.
¹⁰ Program in Bioinformatics, Boston University, Boston, MA, USA; Center for Network Systems Biology, Boston University, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston University, Boston, MA, USA.
¹¹ Center for Network Systems Biology, Boston University, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston University, Boston, MA, USA.
¹² Center for Network Systems Biology, Boston University, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston University, Boston, MA, USA; Departments of Biochemistry and Biology, Boston University, Boston, MA, USA.
¹³ Department of Neurology and Laboratory of Neuroscience, IRCCS, Milan, Italy.
¹⁴ Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Program in Neuroscience, Boston University, Boston, MA, USA. Electronic address: bwolozin@bu.edu.
¹⁵ Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada; Program in Bioinformatics, Boston University, Boston, MA, USA; Center for Network Systems Biology, Boston University, Boston, MA, USA; Department of Biochemistry, Boston University School of Medicine, Boston University, Boston, MA, USA; Departments of Biochemistry and Biology, Boston University, Boston, MA, USA. Electronic address: aemili@bu.edu.

Abstract

Connectivity webs mediate the unique biology of the mammalian brain. Yet, while cell circuit maps are increasingly available, knowledge of their underlying molecular networks remains limited. Here, we applied multi-dimensional biochemical fractionation with mass spectrometry and machine learning to survey endogenous macromolecules across the adult mouse brain. We defined a global "interactome" comprising over one thousand multi-protein complexes. These include hundreds of brain-selective assemblies that have distinct physical and functional attributes, show regional and cell-type specificity, and have links to core neurological processes and disorders. Using reciprocal pull-downs and a transgenic model, we validated a putative 28-member RNA-binding protein complex associated with amyotrophic lateral sclerosis, suggesting a coordinated function in alternative splicing in disease progression. This brain interaction map (BraInMap) resource facilitates mechanistic exploration of the unique molecular machinery driving core cellular processes of the central nervous system. It is publicly available and can be explored here https://www.bu.edu/dbin/cnsb/mousebrain/.

Keywords: ALS; BraInMap; TDP-43; cofractionation/mass spectometry; complexosome; interaction network; machine learning; neurodegeneration; protein-protein interaction.

Publication types

Dataset
Research Support, N.I.H., Extramural

MeSH terms

Amyotrophic Lateral Sclerosis / metabolism
Animals
Brain / metabolism*
Brain Mapping / methods*
Connectome / methods*
DNA-Binding Proteins / genetics
Machine Learning
Mammals / physiology
Mass Spectrometry / methods
Mice
Mutation / genetics

Substances

DNA-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding