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

Autism spectrum disorder (ASD) involves impaired synaptic plasticity tightly coupled to local mRNA translation. Cytoplasmic polyadenylation element-binding proteins 3 and 4 (CPEB3 and CPEB4) are post-transcriptional regulators of neuronal mRNA translation that may contribute to ASD-related molecular alterations. In this theoretical-computational study, we develop a weighted functional impact model that integrates transcriptomic expression with intrinsic molecular constraints of CPEB3 and CPEB4 to estimate regional and cell type-specific vulnerability in ASD. Coarse-grained molecular dynamics (MD) simulations were quantitatively analyzed to assess aggregation, diffusion, and cluster stability under cell type-specific cytoplasmic conditions, with statistical uncertainty explicitly evaluated. The anterior cingulate cortex and thalamus emerged as primary vulnerability sites. Despite higher CPEB4 expression-mainly in glial cells-our weighted functional impact model predicted greater theoretical susceptibility linked to CPEB3 dysfunction, particularly in inhibitory and excitatory neurons. MD simulations revealed that CPEB3 forms transient diffusion-permissive aggregates, whereas CPEB4 tends to assemble into more stable condensates. These complementary behaviors suggest differential but interdependent regulation of neuronal and glial functions. Importantly, the proposed framework provides experimentally testable predictions on how protein-protein interactions, microexon loss, and cytoplasmic crowding influence translational control in ASD. This integrative approach provides a quantitative and biologically grounded framework to investigate how post-transcriptional regulators contribute to ASD-relevant molecular vulnerability.