Aberrant Splicing Signatures Underpin Oligodendrocyte Damage in ALS and Neuron Loss in FTD

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are severe neurodegenerative diseases with overlapping features, including TDP-43 pathology.
• Despite similarities, distinct molecular alterations between ALS and FTD remain poorly understood.

Purpose of the Study:

• To investigate the differential molecular changes, particularly aberrant splicing, in ALS and FTD patients.
• To identify cell-type-specific molecular signatures and potential biomarkers distinguishing ALS from FTD.

Main Methods:

• Integration of bulk and single-nucleus RNA sequencing data from ALS and FTD patient samples.
• Identification and experimental validation of aberrant splicing junctions.
• Analysis of TDP-43 targets and RNA-binding protein contexts in glial cells.

Main Results:

• ALS patients exhibited more severe oligodendrocyte damage, whereas FTD patients showed greater neuron loss.
• Identified 31 oligodendrocyte-specific and 507 neuron-specific aberrant splicing junctions as potential biomarkers.
• Detected de novo peptides from abnormally spliced transcripts in cerebrospinal fluid and elucidated TDP-43's role in glial cells.

Conclusions:

• ALS and FTD present distinct dysfunctional cell populations with unique aberrant splicing signatures.
• These findings provide insights into the differential cellular impacts and molecular mechanisms of ALS and FTD.
• Identified potential biomarkers for disease classification and understanding underlying pathology.