A study by IRB Barcelona unveils how the lack of a fraction of the CPEB4 protein causes a decrease in the expression of genes crucial for neuronal development. Credit IRB Barcelona
Autism is a neurodevelopmental disorder characterized by challenges in communication and social behaviour. About 20% of cases are linked to a specific genetic mutation, while the origin of the remaining 80%, referred to as idiopathic autism, remains unknown.
A team of scientists led by Drs. Raúl Méndez and Xavier Salvatella at the Institute for Research in Biomedicine (IRB Barcelona), has discovered a molecular mechanism that explains why certain alterations in the neuronal protein CPEB4 are linked to idiopathic autism.
The study builds upon previous research published in 2018, which identified CPEB4 as an essential protein in regulating neuronal proteins associated with autism. In that earlier study, researchers found that individuals with autism were missing a specific neuronal microexon, a tiny segment of genetic material vital for proper protein function in neurons. The new findings published in the journal Nature highlight the significance of this tiny fragment in neuronal activity, as it allows CPEB4 to form and disassemble protein condensates effectively.
“This study offers new insights into how minor modifications in proteins that regulate gene expression can significantly influence neuronal development. This discovery opens up new avenues for exploring future therapies,” explains Dr Méndez, an ICREA researcher and head of the Translational Control of Cell Cycle and Differentiation laboratory at IRB Barcelona.
Molecular condensates and gene regulation
The region of the CPEB4 protein that holds the segment lacks a well-defined three-dimensional structure. Proteins with disordered regions can form condensates, like tiny droplets within the cell where molecules, such as messenger RNAs (mRNAs) that code for other proteins involved in neuronal function, are stored in a silenced state. These condensates can assemble and disassemble in response to cellular signals, enabling dynamic regulation of gene expression.
“In this study, we have discovered that this neuronal microexon is essential for maintaining the stability and dynamics of the condensates formed by CPEB4 in neurons. Without the microexon, these condensates become less dynamic and can aggregate into solid forms that do not function properly,” says Dr Salvatella, an ICREA researcher and head of the Laboratory of Molecular Biophysics at IRB Barcelona.
This lack of dynamism prevents the mRNAs stored in these condensates from being released when neurons are stimulated, leading to decreased production of proteins essential for neuronal development and function. Among these mRNA molecules are many genes previously linked to autism.
Implications for neuronal development
Proper regulation of these genes is essential during brain development. If these CPEB4 condensates do not function correctly due to the absence of the neuronal micro exon, disruptions of neuronal development can occur, manifesting as symptoms of autism. The described mechanism also helps to explain the complexity and heterogeneous nature of idiopathic autism, as this spectrum includes multiple manifestations and varying degrees of severity.
“Our results suggest that even small decreases in the percentage of microexon inclusion can have significant effects. This would explain why some individuals without a gene mutation develop idiopathic autism,” explain Drs: Carla Garcia-Cabau and Anna Bartomeu, IRB Barcelona researchers and first authors of the study.
The concept proposed in this study of gene regulation in neurons through the formation of condensates may also have implications for ageing. Over time, these condensates lose their plasticity, meaning their capacity to assemble and disassemble, which could impair proper neuronal function and promote the development of neurodegenerative diseases.
Possible avenues for future therapies
One of the study’s promising findings is that micro exon 4 appears to work “in trans,” which means that it might be possible to introduce this small sequence of amino acids into cells to partially restore CPEB4 function and potentially reverse the symptoms.
“Although we’re still in exploratory stages, this discovery is promising and points to a potential therapeutic approach that could restore CPEB4 function,” says Dr. Méndez. The researchers emphasise that this finding still requires extensive experimental testing, such as studies in animal models and overcoming multiple technical barriers.