RNA epitranscriptomics dysregulation: A major determinant for significantly increased risk of ASD pathogenesis

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics and Epigenetics

Background:

• Autism spectrum disorders (ASDs) are severe, heterogeneous neurodevelopmental conditions with unclear pathogenesis.
• While genetic and epigenetic factors are implicated, the precise mechanisms disrupting cortical circuits in ASD remain largely unknown.
• Altered neurodevelopmental patterns are central to ASD, affecting brain function and connectivity.

Purpose of the Study:

• To explore the hypothesis that RNA epitranscriptomics may be a primary driver in autism spectrum disorder (ASD) pathogenesis.
• To investigate the role of RNA epitranscriptomic mechanisms in altering spatiotemporal protein expression during fetal brain development.
• To understand how these mechanisms, influenced by genetics and environment, contribute to ASD heterogeneity.

Main Methods:

• Review and theoretical exploration of existing postulates on ASD pathogenesis.
• Analysis of RNA epitranscriptomic mechanisms, including mRNA modifications and RNA interference (RNAi).
• Examination of the interplay between genotype, environment, and RNA modifications in central nervous system (CNS) development.

Main Results:

• RNA epitranscriptomic mechanisms, including mRNA epitranscriptomics and RNAi, can alter protein expression quantitatively and qualitatively.
• These mechanisms are sensitive to environmental factors like maternal inflammation, impacting fetal brain development.
• RNA epitranscriptomics may precede or significantly influence epigenetic modifications in ASD pathogenesis.

Conclusions:

• RNA epitranscriptomics offers a potential explanation for the heterogeneity observed in ASD, impacting receptor and channel protein expression.
• Dysregulation in early RNA epitranscriptomic processes can lead to widespread neuropathological alterations.
• This framework highlights RNA epitranscriptomics as a crucial factor in understanding ASD etiology and its complex presentation.