Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons

Summary: Loss of the nuclear RNA binding protein TAR DNA binding protein-43 (TDP-43) into cytoplasmic aggregates is the strongest correlate to neurodegeneration in amyotrophic lateral sclerosis and frontotemporal degeneration. The molecular changes associated with the loss of nuclear TDP-43 in human tissues are not entirely known. Using subcellular fractionation and fluorescent-activated cell sorting to enrich for diseased neuronal nuclei without TDP-43 from post-mortem frontotemporal degeneration-amyotrophic lateral sclerosis (FTD-ALS) human brain, we characterized the effects of TDP-43 loss on the transcriptome and chromatin accessibility. Nuclear TDP-43 loss is associated with gene expression changes that affect RNA processing, nucleocytoplasmic transport, histone processing, and DNA damage. Loss of nuclear TDP-43 is also associated with chromatin decondensation around long interspersed nuclear elements (LINEs) and increased LINE1 DNA content. Moreover, loss of TDP-43 leads to increased retrotransposition that can be inhibited with antiretroviral drugs, suggesting that TDP-43 neuropathology is associated with altered chromatin structure including decondensation of LINEs. : Liu et al. fractionated and sorted for diseased neuronal nuclei from post-mortem FTD-ALS human brains and showed that loss of an RNA-binding protein, TDP-43, altered the transcriptome and chromatin accessibility. Their results suggest that loss of nuclear TDP-43 is associated with decondensation of LINE retrotransposons. Keywords: frontotemporal dementia, motor neuron disease, amyotrophic lateral sclerosis, RNA, chromatin, ATAC-seq, autoregulation, splicing, histone, reverse transcriptas