International Business Department           Liu Bojia           December 16, 2024

  Autism Spectrum Disorder (ASD), also known as autism or autism, is a group of neurodevelopmental disorders typified by difficulties in communication and social behaviour that typically emerge in childhood and persist into adulthood. According to the Centers for Disease Control and Prevention (CDC) in recent years, 2.76% of children in the United States have autism, and an estimated 2.21% of adults also have autism. China reported a prevalence of about 0.7 per cent in children aged 6-12 in 2013, in addition to the many patients who go unrecognised and undiagnosed. (An autism scale developed by the University of Cambridge's Centre for Autism Research is available at the end of this article for interested readers to scan for professional testing.)

  Today, the level of interest in autism is rising, but the pathogenesis of autism remains largely unresolved. Currently, about 20 per cent of autism cases have been found to be associated with specific genetic mutations, but the origin of the remaining 80 per cent of cases remains a mystery, and these cases of unknown etiology are also known as idiopathic autism.

  Recently, a team led by the Institute of Biomedical Research in Barcelona unravelled a key molecular mechanism of autism in a Nature paper. It was found that the deletion of a tiny modification in a segment of the CPEB4 protein leads to a decrease in the expression of genes that are essential for neuronal development, ultimately triggering autism. The discovery also lays the foundation for targeted therapies for autism.

  Let's first turn the clock back to 2018, when the team, in another Nature paper, found that the CPEB4 protein, an RNA-binding protein that regulates the translation process through changes in the length of the poly(A) tail of the adenylate strand in mRNAs, plays an important role in neurodevelopment, learning and memory, among other things, was strongly associated with autism. The team noted that in CPEB4 from patients with idiopathic autism, the insertion of a neuron-specific microexon (me4), a segment of 24 nucleotides, was reduced. Microexons are genetic material critical for protein function in neurons, but the mechanism by which the reduction in me4 leads to misregulation of gene expression in autism is unknown.

  Building on the 2018 study, the latest research explores the role of this microexon further. It was found that the CPEB4 protein containing the me4 fragment can form a reversible cohesion in neurons. When neuronal depolarisation is activated, these condensates are re-dissolved due to changes in intracellular pH that alter the balance of interactions of the stable condensate, releasing mRNAs that promote the synthesis of proteins required for neuronal development and function, leading to dynamic regulation of gene expression.

  But when me4 is absent, such a dynamic regulatory balance is disrupted. At this time CPEB4 forms aggregates that accumulate in the brain, and they cannot be dissolved even when neurons are depolarised. The inability of these key proteins to function properly due to blocked mRNA release can lead to disrupted neuronal development and ultimately autism symptoms.

  It is worth noting that the study found that even just a slight decrease in the proportion of CPEB4 containing me4 fragments can have a significant impact on normal neuronal development. In this way, the study may explain why some individuals who do not show the genetic mutation can also develop idiopathic autism.

  In addition, this study provides a new explanation for the deterioration of neurological function during the aging process. Since normal neural function cannot be achieved without the reversible regulation of CPEB4 condensate, with age, once the plasticity of CPEB4 condensate decreases, the erroneous accumulation of CPEB4 protein may impair normal neural function and trigger neurodegenerative diseases.

  The discovery of this novel pathogenic mechanism undoubtedly points to a completely new path for the treatment of autism. Since me4 plays a role in the transcription process, the research team designed a synthetic peptide containing the me4 sequence, and they found that the synthetic peptide improved the thermodynamic stability of the condensate and reduced the accumulation of CPEB4 errors. Thus, this synthetic peptide strategy is expected to restore CPEB4 function and reverse symptoms.

  In doing so, this study takes an important step towards understanding the molecular mechanisms of idiopathic autism, revealing how small modifications to proteins can have a major impact on neuronal function. These findings also open up potential new pathways for the development of autism therapies.