Convergent cerebrospinal fluid proteomes and metabolic ontologies in humans and animal models of Rett syndrome

• Type of Material: Article
• Authors: Stephanie A. Zlatic, Emory University; Duc Duong, Emory University; Kamal K.E. Gadalla, Edinburgh Medical School; Brenda Murage, Edinburgh Medical School; Lingyan Ping, Emory University; Ruth Shah, University of Edinburgh; James J. Fink, Q-State Biosciences, Inc.; Omar Khwaja, Children's Hospital Boston; Lindsay C. Swanson, Children's Hospital Boston; Mustafa Sahin, Children's Hospital Boston; Sruti Rayaprolu, Emory University; Prateek Kumar, Emory University; Srikant Rangaraju, Emory University; Adrian Bird, University of Edinburgh; Daniel Tarquinio, Emory University; Randall Carpenter, Rett Syndrome Research Trust; Stuart Cobb, Edinburgh Medical School; Victor Faundez, Emory University
• Language: English
• Date: 2022-09-16
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Author(s)
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.isci.2022.104966
• Title of Journal or Parent Work: iScience
• Volume: 25
• Issue: 9
• Start Page: 104966
• End Page: 104966
• Grant/Funding Information: VF was funded by the Rett Syndrome Research Trust, the Loulou Foundation, and NIH 1RF1AG060285. S Rangaraju was partly funded by the NIH (5R01NS114130). S Rayaprolu was partly supported by the NIH (F32 AG064862).SC was funded by the Rett Syndrome Research Trust and Simons Initiative for the Developing Brain. JJF was funded by the Rett Syndrome Research Trust. VF is grateful for mitochondria provided by Maria Olga Gonzalez.
• Keywords: Proteomics; Pathophysiology; Clinical neuroscience; Disease
• Research Categories: Health Sciences, Pathology; Biology, Physiology

Abstract

MECP2 loss-of-function mutations cause Rett syndrome, a neurodevelopmental disorder resulting from a disrupted brain transcriptome. How these transcriptional defects are decoded into a disease proteome remains unknown. We studied the proteome of Rett cerebrospinal fluid (CSF) to identify consensus Rett proteome and ontologies shared across three species. Rett CSF proteomes enriched proteins annotated to HDL lipoproteins, complement, mitochondria, citrate/pyruvate metabolism, synapse compartments, and the neurosecretory protein VGF. We used shared Rett ontologies to select analytes for orthogonal quantification and functional validation. VGF and ontologically selected CSF proteins had genotypic discriminatory capacity as determined by receiver operating characteristic analysis in Mecp2-/y and Mecp2−/+. Differentially expressed CSF proteins distinguished Rett from a related neurodevelopmental disorder, CDKL5 deficiency disorder. We propose that Mecp2 mutant CSF proteomes and ontologies inform putative mechanisms and biomarkers of disease. We suggest that Rett syndrome results from synapse and metabolism dysfunction.