Widespread RNA hypoediting in schizophrenia and its relevance to mitochondrial function

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• RNA editing alterations are observed in neurological genes in schizophrenia (SCZ).
• The global profile and molecular functions of RNA editing in SCZ are not fully understood.

Purpose of the Study:

• To analyze the global RNA editing profile in postmortem brains of SCZ patients.
• To identify SCZ-associated RNA editing sites and their molecular functions, particularly their link to mitochondrial processes.

Main Methods:

• Analysis of RNA editing in four SCZ cohorts using postmortem brain tissue.
• Weighted Gene Co-expression Network Analysis (WGCNA) to identify disease-associated editing sites.
• Massively parallel reporter assays and bioinformatic analyses to assess the impact of 3'UTR editing on gene expression.
• Functional characterization of recoding sites in the mitofusin 1 (MFN1) gene.

Main Results:

• A significant and reproducible trend of RNA hypoediting was observed in SCZ patients of European descent.
• A set of SCZ-associated editing sites was identified, shared across cohorts.
• Differential 3' untranslated region (3'UTR) editing sites influencing host gene expression were enriched for mitochondrial processes.
• Two recoding sites in MFN1 were characterized, demonstrating functional relevance to mitochondrial fusion and cellular apoptosis.

Conclusions:

• Schizophrenia is associated with a global reduction in RNA editing.
• RNA editing plays a role in mitochondrial function and cellular apoptosis in SCZ.
• Altered RNA editing, particularly hypoediting, represents a significant molecular mechanism in schizophrenia.