Individuals with autism spectrum disorder (ASD) process information differently from neurotypical individuals. They also carry DNA-damaging rare variants, especially de novo mutations, in certain genes more than expected by chance. Whole-exome studies, for instance, associate a broad set of genes with ASD, many of them involved in synaptic structure and function, while others regulate gene expression in some way, such as by chromatin-remodeling pathways. Transcriptomic investigations of brain tissue from individuals with ASD, largely focused on cortical regions, also find diverse pathways associated with ASD.

Synapse and circuit maturation are regulated by protein isoform expression across development, with different isoforms displaying distinct functional properties. When both the transcriptome and proteome are characterized in the same individual and tissue, the correlation of these two omics measures is modest at best. Thus, to observe the full impact of ASD genetic risk on the protein networks that drive synapse and circuit maturation, these protein networks must be directly investigated.

Combining quantitative proteomics with sophisticated bioinformatics and statistics, Matthew MacDonald, Bernie Devlin and Kathryn Roeder have found evidence for altered expression and synaptic localization of 20 to 30 percent of almost 5,000 proteins in the primary visual cortex (V1) of individuals with ASD compared to neurotypical individuals (preliminary results) across postnatal development. This list of proteins (a) was significantly enriched for synaptic genes (SYNGO, q = 8.4×10-4); (b) recapitulated findings at the transcript level from a prior RNAseq analysis of V1 in an overlapping cohort, while also identifying novel alterations in protein expression and synaptic localization independent of transcript levels; and (c) specifically implicated impairments in V1 cortico-cortico, but not thalamo-cortico, circuits in ASD.

Thus, the team posits that large-scale integration of the transcriptome and proteome, interpreted in light of genetic findings, will be essential to more completely map the effects of ASD genetics on the protein networks that directly regulate the synapse and circuit alterations believed to underlie ASD symptoms.

To achieve this goal, the team will quantify thousands of transcript and protein levels in postmortem V1 and lateral geniculate nucleus (LGN) tissue (implicated in ASD symptoms) from 100 ASD and 100 neurotypical individuals. This resource will be analyzed to identify and nominate protein networks and cell types that could drive ASD, creating a resource for the research community. Some of this work will be done in collaboration with Daniel Geschwind, Michael Gandal and Dorothy Schafer.