Imagine you’re trying to solve a puzzle, but you only have a few pieces. To make matters worse, the pieces come from different puzzles. This is similar to the challenge researchers face when trying to understand autism spectrum disorder (ASD). In the quest for effective treatments, scientists compared the synaptic proteomes of five different mouse models for autism. They discovered striking similarities between these models, suggesting common molecular pathways at play in ASD. Using advanced mass spectrometry techniques, researchers found deficits in oxidative phosphorylation and Rho GTPase signaling in all the tested mouse models. This means that even though each model represents distinct genetic changes, they converge on these key pathways affecting neuronal synapses. These findings provide valuable insights into the complex mechanisms underlying ASD and lay the foundation for uncovering molecular subtypes within the disorder. By exploring these shared pathways, scientists may unlock new therapeutic targets for tailored treatments. To dive deeper into this fascinating research, check out the full article!

Specific and effective treatments for autism spectrum disorder (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 common 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 at the synapse, including changes in oxidative phosphorylation, and Rho family small GTPase signaling. Functional validation of one of these aberrant pathways, Rac1 signaling, confirms that the ANKS1B model displays 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 pathogenesis of this disorder.

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