TDP-43 toxic gain of function links ALS, FTD and Alzheimers Disease through splicing dysregulation

TDP-43 proteinopathy is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). It is also common in Alzheimers disease (AD), but its functional consequences are unclear. Here, we show that TDP-43 pathology in AD is broadly associated with splicing abnormalities. We define a conserved TDP-43-dependent splicing signature in AD and identify AD-relevant TDP-43-dependent mis-spliced mRNAs, including amyloid precursor protein (APP). TDP-43 drives the formation of elongated APP isoforms, disrupting alternative splicing across ALS, FTLD-TDP and AD, thus providing a compelling mechanism for a long-standing observation of APP isoform dysregulation. APP isoform imbalance correlates with and partially mediates the association between TDP-43 pathology and A{beta} burden pathology and is depicted spatially with pTDP-43 and malspliced STMN2 in LATE hippocampus. Contrary to a pure nuclear loss-of-function model, mis-splicing is driven by cytoplasmic TDP-43 gain-of-function that co-sequesters RNA-binding proteins involved in the regulation of splicing. Knockdown of TDP-43-associated RNA-binding proteins recapitulates disease-relevant splicing changes in AD and ALS/FTLD-TDP; furthermore, at least some of these proteins colocalize with cytoplasmic pTDP-43 in neuropathological samples. Together, our findings establish cytoplasmic TDP-43-driven splicing dysfunction as a key component of neurodegeneration, define sets of disease-relevant mis-spliced RNA across AD, and unite AD with ALS/FTLD-TDP through a shared mechanism of splicing factor sequestration.