Transcriptome-wide alternative splicing and transcript-level differential expression analysis of post-mortem Lewy...

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Lewy body dementias (LBD) are the second most common dementia, with poorly understood molecular pathology.
• RNA splicing dysregulation is prevalent in LBD brains, suggesting a role in disease mechanisms.

Purpose of the Study:

• To conduct the first transcriptome-wide, transcript-level differential expression analysis in post-mortem LBD brains.
• To identify novel therapeutic targets and biomarkers for LBD by examining RNA alterations.

Main Methods:

• Utilized next-generation RNA-sequencing data from anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) of LBD patients and controls.
• Employed Salmon for transcript quantification, edgeR for differential expression analysis, and DRIMseq for alternative splicing analysis.

Main Results:

• Identified 74 differentially expressed transcripts (DET) in ACC and 96 in DLPFC.
• Discovered 135 alternatively spliced genes in ACC and 98 in DLPFC of LBD brains.
• Found DET potentially impacting DNA repair, apoptosis, neuroplasticity, and RNA regulation.

Conclusions:

• Transcript-level analysis reveals DET missed by gene-level studies, offering deeper insights into LBD molecular pathology.
• Widespread alternative splicing is confirmed, with no evidence of chronic neuroinflammation.
• Specific DET, particularly from TMEM18, MICB, MPO, and GABRB3, show promise as LBD biomarkers and therapeutic targets.