TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in amyotrophic lateral sclerosis and frontotemporal dementia.

To determine the biological relevance of TDP-43-regulated APA, we studied its effects on microtubule affinity regulating kinase 3 (MARK3), a highly significant ( P = 9.4 × 10 –16 ) hit from APA analysis of ALS/FTD frontal cortex neuron nuclei containing or depleted of TDP-43.

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We similarly found that TDP-43 depletion in iPSC-MNs corresponds with a strong trend ( P = 0.069) toward increased tau S262 phosphorylation ( Supplemental Figure 10A ).

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While we observed a small increase in the relative expression of the long 3′ UTR MARK3 isoform in TDP-43 proteinopathy patient tissue, this did not reach statistical significance ( Supplemental Figure 9C ).

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