Alcohol use disorder causes global changes in splicing in the human brain

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alcohol use disorder (AUD) is a prevalent condition causing cognitive decline.
• The precise mechanisms by which alcohol affects brain function remain unclear.
• RNA splicing is crucial for transcriptome formation and cellular function.

Purpose of the Study:

• To investigate whether AUD leads to impaired RNA splicing in specific human brain regions.
• To identify potential molecular mechanisms underlying alcohol-induced splicing alterations.

Main Methods:

• Analysis of RNA sequencing data (bam files) from superior frontal cortex (SFC), nucleus accumbens (NA), basolateral amygdala (BLA), and central nucleus of the amygdala (CNA).
• Utilized rMATS software for splicing event detection.
• Employed Gene Ontology, Gene Set Enrichment Analysis, and LncRNA Ontology for pathway analysis.
• Examined expression of spliceosome components, including small nuclear RNAs (snRNAs) and splicing factors like HSPA6.

Main Results:

• AUD was associated with limited changes in gene expression across the studied brain regions.
• A significant number of mis-splicing events were detected in all investigated brain areas (SFC, NA, BLA, CNA).
• Expression of splicing factor HSPA6 was significantly increased in SFC, BLA, and CNA.
• Aberrant expression of splicing-related long noncoding RNAs (lncRNAs) was observed in AUD.

Conclusions:

• Alcohol use disorder induces widespread and profound changes in RNA splicing patterns in the human brain.
• These splicing alterations may be driven by the dysregulation of specific splicing factors, such as HSPA6.
• Altered expression of lncRNAs involved in splicing regulation likely contributes to the observed mis-splicing in AUD.