MassIVE MSV000091848

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Comparing synaptic proteomes across five mouse models for autism reveals converging molecular similarities including deficits in oxidative phosphorylation and Rho GTPase signaling

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Description

Specific and effective treatments for autism spectrum disorders (ASD) are lacking due to a poor understanding of disease mechanisms. Here, we test the idea that similarities between diverse ASD mouse models are caused by deficits in shared molecular pathways at neuronal synapses. To do this, we leverage the availability of multiple genetic models of ASD that exhibit shared synaptic and behavioral deficits and use quantitative mass spectrometry with isobaric tandem mass tagging (TMT) to compare their hippocampal synaptic proteomes. Comparative analyses of mouse models for Fragile X syndrome (Fmr1 knockout), cortical dysplasia focal epilepsy syndrome (Cntnap2 knockout), PTEN hamartoma tumor syndrome (Pten haploinsufficiency), ANKS1B syndrome (Anks1b haploinsufficiency), and idiopathic autism (BTBR+) revealed several common altered cellular and molecular pathways atthe synapse, including changes in oxidative phosphorylation, endocytosis, and Rho family small GTPase signaling. Functional validation of one of these aberrant pathways, Rac1 signaling, confirms that ANSK1B models display altered Rac1 activity counter to that observed in other models, as predicted by the bioinformatic analyses. Overall similarity analyses reveal clusters of synaptic profiles, which may form the basis for molecular subtypes that explain genetic heterogeneity in ASD despite a common clinical diagnosis. Our results suggest that ASD-linked susceptibility genes ultimately converge on common signaling pathways regulating synaptic function and propose that these points of convergence are key to understanding the human disease. [doi:10.25345/C5N01040K] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: proteomic, PSD, autism, mouse model, Rho GTPase, Rac, tandem mass tags, TMT, 28 comparative, multiple ASD models

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Principal Investigators:
(in alphabetical order) 		Dr. Bryen A. Jordan, Albert Einstein College of Medicine, U.S.A
Dr. Thomas A. Neubert, New York University School of Medicine, USA
Submitting User: hbromage
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