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

Zlatic, SA, Duong, D, Gadalla, KKE ORCID: https://orcid.org/0000-0002-1657-8953, Murage, B, Ping, L, Shah, R, Fink, JJ, Khwaja, O, Swanson, LC, Sahin, M, Rayaprolu, S, Kumar, P, Rangaraju, S, Bird, A, Tarquinio, D, Carpenter, R, Cobb, S and Faundez, V, 2022. Convergent cerebrospinal fluid proteomes and metabolic ontologies in humans and animal models of Rett syndrome. iScience, 25 (9): 104966. ISSN 2589-0042

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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.

Item Type:	Journal article
Publication Title:	iScience
Creators:	Zlatic, S.A., Duong, D., Gadalla, K.K.E., Murage, B., Ping, L., Shah, R., Fink, J.J., Khwaja, O., Swanson, L.C., Sahin, M., Rayaprolu, S., Kumar, P., Rangaraju, S., Bird, A., Tarquinio, D., Carpenter, R., Cobb, S. and Faundez, V.
Publisher:	Elsevier
Date:	16 September 2022
Volume:	25
Number:	9
ISSN:	2589-0042
Identifiers:	Number Type 10.1016/j.isci.2022.104966 DOI S2589-0042(22)01238-X Publisher Item Identifier 1807927 Other
Rights:	This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	25 Sep 2023 09:43
Last Modified:	25 Sep 2023 09:43
URI:	https://irep.ntu.ac.uk/id/eprint/49798

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