Differential exon usage and cryptic exon profiles of TDP-43 loss of function in amyotrophic lateral sclerosis brain tissue

TDP-43 dysfunction is a molecular hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major hypothesis of TDP-43 dysfunction in disease is the loss of normal nuclear function, resulting in impaired RNA regulation and the emergence of cryptic exons. Cryptic exons and exon changes are emerging as promising markers of lost TDP-43 function in addition to revealing biological pathways involved in neurodegeneration in ALS/FTD. Here, we investigated TDP-43 loss of function by depleting TARDBP from human post-mortem brain pericytes and identifying differential exon usage events with RNA-sequencing analysis. Differential exon usage events validated by qPCR were compiled into a panel with other well-established TDP-43 loss-of-function exon markers and then tested in ALS and control motor cortex tissue. We find that profiles of TDP-43-related cryptic exons and changed exon usage discriminate ALS brain tissue from controls, and propose that splicing panels may have predictive value for therapeutic intervention. ### Competing Interest Statement The authors have declared no competing interest.