Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alternative splicing of microexons in neuronal proteins is common but poorly understood.
• Altered microexon inclusion is linked to neurodevelopmental disorders, including autism spectrum disorder (ASD).
• A specific microexon in CPEB4 has been previously linked to idiopathic ASD.

Purpose of the Study:

• To elucidate the function of a neuron-specific microexon in CPEB4.
• To understand how microexon inclusion influences CPEB4's role in gene regulation.
• To investigate the mechanism by which microexon changes affect ASD-linked gene expression.

Main Methods:

• Investigated CPEB4 protein condensation and dissolution dynamics in neurons.
• Analyzed the role of heterotypic and homotypic interactions involving the microexon and histidine residues.
• Examined the impact of microexon inclusion on CPEB4-mediated translational control.

Main Results:

• Neuronal CPEB4 forms condensates that reversibly dissolve upon depolarization.
• The microexon, through heterotypic interactions, prevents irreversible CPEB4 aggregation by competing with homotypic histidine interactions.
• This mechanism ensures reversible regulation of gene expression in response to neuronal activity.

Conclusions:

• The 24-nucleotide microexon in CPEB4 is essential for maintaining reversible translational control in neurons.
• This microexon prevents protein aggregation, preserving the dynamic regulation of gene expression vital for neuronal function.
• Dysregulation of this microexon's inclusion can disrupt gene expression, contributing to neurodevelopmental disorders like ASD.