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

ABSTRACT Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two severe diseases sharing similar genetic, pathological, and clinical features, including TDP‐43 pathology. However, differences in molecular changes between ALS and FTD remain elusive. Here, integrating large sets of bulk and single‐nucleus RNA‐seq from ALS/FTD patients revealed expression and splicing changes indicating more severe oligodendrocyte damage in ALS than FTD, and more significant neuron loss in FTD. Specifically, we identified 31 oligodendrocyte‐specific and 507 neuron‐specific aberrant splicing junctions as potential biomarkers with robust classification performance, and experimentally validated a novel target in patient tissues. Moreover, we found that abnormally spliced transcripts produced de novo peptides in patients’ cerebrospinal fluids. Importantly, we further identified the targets of TDP‐43 in glial cells and decoded the differential RNA‐binding protein (RBP) contexts of TDP‐43‐regulated aberrant splicing. These findings uncover that ALS and FTD patients have distinct dysfunctional cell populations harboring specific aberrant splicing signatures, suggesting varying cellular impacts and providing potential biomarkers and insights into molecular mechanisms underlying ALS/FTD.