Modeling the functional impact of CPEB3 and CPEB4 dysregulation in autism: A theoretical-computational framework

Area of Science:

• Neuroscience
• Computational Biology
• Genetics

Background:

• Autism spectrum disorder (ASD) is linked to impaired synaptic plasticity and local mRNA translation.
• Cytoplasmic polyadenylation element-binding proteins (CPEB3 and CPEB4) are key regulators of neuronal mRNA translation, potentially involved in ASD.
• Understanding the molecular mechanisms underlying ASD vulnerability is crucial for developing targeted interventions.

Purpose of the Study:

• To develop a weighted functional impact model integrating transcriptomic data and CPEB3/CPEB4 molecular properties.
• To estimate regional and cell type-specific vulnerability in ASD.
• To investigate the role of CPEB3 and CPEB4 in ASD-related molecular alterations.

Main Methods:

• Developed a weighted functional impact model.
• Integrated transcriptomic expression data with intrinsic molecular constraints of CPEB3 and CPEB4.
• Performed coarse-grained molecular dynamics (MD) simulations to analyze protein aggregation, diffusion, and cluster stability.

Main Results:

• The anterior cingulate cortex and thalamus were identified as primary vulnerability sites in ASD.
• Despite higher CPEB4 expression in glial cells, CPEB3 dysfunction showed greater predicted susceptibility in neurons.
• MD simulations indicated CPEB3 forms transient aggregates, while CPEB4 forms stable condensates, suggesting differential regulatory roles.

Conclusions:

• The study provides a quantitative framework for investigating post-transcriptional regulators in ASD.
• Findings highlight the differential yet interdependent roles of CPEB3 and CPEB4 in neuronal and glial functions.
• The model offers experimentally testable predictions regarding factors influencing translational control in ASD.