Integrated cortical and plasma proteomic analysis of Cntnap2 knockout mice and human models of autism spectrum disorder: Potential involvement of galectin-3-binding protein.

Scientists studied brain and blood proteins in mice with autism-like traits and people with autism. They found a protein called LGALS3BP that was increased in both groups. This protein might help doctors identify autism through blood tests in the future, but much more research is needed with larger groups of people.

This preclinical study compared protein profiles in brain tissue and blood samples from Cntnap2 knockout mice (an autism model) and individuals with autism spectrum disorder. Researchers analyzed differentially expressed proteins and identified two common candidates: downregulated C1QB and upregulated galectin-3-binding protein (LGALS3BP). Western blotting validation confirmed increased LGALS3BP expression in both brain and blood of knockout mice, though C1QB downregulation was not validated. The findings suggest LGALS3BP may serve as a potential biomarker for ASD and indicate both central nervous system and peripheral mechanisms contribute to autism pathophysiology.

However, sample sizes were very small (n=3 per group initially), limiting generalizability.

LGALS3BP shows promise as a blood-based biomarker for ASD, potentially enabling earlier or more accessible diagnosis. However, extensive validation in diverse populations is required before clinical application.

Very small sample sizes (n=3 initially), preliminary findings requiring validation in larger populations, limited to single mouse model, unclear generalizability across autism heterogeneity.

Despite decades of research, the etiology of autism spectrum disorder (ASD) remains largely uncomprehended, probably due to its clinical and phenotypic heterogeneity. Animal models, particularly contactin-associated protein-like 2 (Cntnap2) knockout (KO) mice, have been instrumental in elucidating ASD-related neurobiological mechanisms, as they exhibit ASD-like phenotypes, such as impaired social interactions in sociability paradigms. This provides the possibility for identifying detectable protein-based biomarkers that may assist in ASD diagnosis. Herein, we implemented an integrated approach to analyze the plasma and prefrontal cortex (PFC) proteomes exclusively from Cntnap2 KO mice (n = 3) or patients diagnosed with ASD (n = 3), along with gene ontology (GO) functional enrichment and pathway analysis.

Overlapping GO terms and pathways were identified from the proteomic subsets of Cntnap2 KO mice plasma and PFC after dividing differentially expressed proteins (DEPs) into upregulated and downregulated subsets. Overlapping GO terms and pathways were further identified following the comparison of the upregulated and downregulated DEPs found in the plasma of patients with ASD. Under these GO terms and pathways, two (2) common DEPs were identified: downregulated complement C1q subcomponent subunit B (C1QB) and upregulated galectin-3-binding protein (LGALS3BP). The upregulated expression of LGALS3BP, but not C1QB downregulation, in the PFC and blood of Cntnap2 KO mice (n = 12-13) were validated through Western blotting.

While future investigations will include other preclinical ASD models and clinically heterogeneous human populations, overall, these preliminary findings suggest a potential role for LGALS3BP as a biomarker for ASD and support the involvement of both central and peripheral mechanisms in its pathophysiology.