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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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Dr. Thomas A. Neubert Dr. Bryen A. Jordan

PROVIDER: MSV000091848 | MassIVE | Wed May 03 13:22:00 BST 2023

REPOSITORIES: MassIVE

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Project description:Austism spectrum disorder (ASD) is a heterogeneous behavioral disease most commonly characterized by severe impairment of social engagement and the presence of repetitive activities. The molecular etiology of ASD is still largely unknown despite a strong genetic component. Part of the difficulty in turning genetics into disease mechanisms and potentially new therapeutics is the sheer number and diversity of the genes that have been associated with ASD and ASD symptoms. The goal of this work is to use shRNA-generated models of genetic defects proposed as causative for ASD to identify the common pathways that might explain how they produce a common clinical outcome. Transcript levels of Mecp2, Mef2a, Mef2d, Fmr1, Nlgn1, Nlgn3, Pten, and Shank3 were knocked-down in mouse primary neuron cultures using shRNA/lentivirus constructs. Whole genome expression analysis was conducted for each of the knock-down cultures as well as a mock-transduced culture and a culture exposed to a lentivirus expressing luciferase. Gene set enrichment and a causal reasoning engine were employed to indentify pathway level perturbations generated by the transcript knock-down. Quantitation of the shRNA targets confirmed the successful knock-down at the transcript and protein levels of at least 75% for each of the genes. After subtracting out potential artifacts caused by transfection and viral infection, gene set enrichment and causal reasoning engine analysis showed that a significant number of gene expression changes mapped to pathways associated with neurogenesis, long-term potentiation, and synaptic activity. This work demonstrates that despite the complex genetic nature of ASD, there are common molecular mechanisms that connect many of the best established autism candidate genes. By identifying the key regulatory checkpoints in the interlinking transcriptional networks underlying autism, we are better able to discover the ideal points of intervention that provide the broadest efficacy across the diverse population of autism patients. n=4 per group. Luciferase shRNA used as control group for shRNA to various gene targets.

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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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