December 4, 2020

An aberrant cytoplasmic intron retention programme is a blueprint for ALS-related RBP mislocalization

Intron retention is known to regulate gene expression. We recently described intron retention as the predominant splicing programme characterizing early stages of motor neurogenesis from human induced pluripotent stem cells (hiPSCs) and it’s perturbation in familial amyotrophic lateral sclerosis (ALS). Here, we sought to gain more insight into the nucleocytoplasmic distribution of aberrant intron-retaining transcripts (IRTs) and to identify their discriminating molecular features. We combined cellular fractionation with hiPSCs undergoing motor neurogenesis and deep-sequenced 95 samples: ALS vs control hiPSCs and nuclear vs cytoplasmic compartments across six timepoints, which represents a rich transcriptomic resource for basic and applied neuroscientists. Using this resource, we identified >100 aberrant cytoplasmic IRTs in cultures carrying ALS-causing VCP gene mutations. We taxonomized aberrant IRTs by their nucleocytoplasmic distribution and demonstrate that these classes exhibit sequence-specific attributes and differential predicted binding affinity to ALS-related RNA binding proteins. In summary we uncover a distinct class of cytoplasmic IRTs that serve as blueprints for established molecular hallmarks of ALS (nuclear-to-cytoplasmic mislocalisation of TDP-43, SFPQ and FUS) and therefore may also represent therapeutic targets.

 bioRxiv Subject Collection: Neuroscience

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