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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE126543 | GEO | 2019/03/15

REPOSITORIES: GEO

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

Project description: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.

| S-EPMC6508629 | biostudies-literature

Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons [RNA-Seq]

Project description: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 a novel subcellular fractionation and fluorescent activated cell sorting method to enrich for diseased neuronal nuclei without TDP-43 from post-mortem 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 was 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.

2019-03-15 | GSE126542 | GEO

Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons [ATAC-Seq]

Project description: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 a novel subcellular fractionation and fluorescent activated cell sorting method to enrich for diseased neuronal nuclei without TDP-43 from post-mortem 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 was 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.

2019-03-15 | GSE126541 | GEO

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

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

| PRJNA522290 | ENA

Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons [RNA-Seq]

Project description:Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons [RNA-Seq]

| PRJNA522295 | ENA

Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons [ATAC-Seq]

Project description:Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons [ATAC-Seq]

| PRJNA522296 | ENA

Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death.

Project description:While cytoplasmic aggregation of TDP-43 is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia, how aggregates form and what drives its nuclear clearance have not been determined. Here we show that TDP-43 at its endogenous level undergoes liquid-liquid phase separation (LLPS) within nuclei in multiple cell types. Increased concentration of TDP-43 in the cytoplasm or transient exposure to sonicated amyloid-like fibrils is shown to provoke long-lived liquid droplets of cytosolic TDP-43 whose assembly and maintenance are independent of conventional stress granules. Cytosolic liquid droplets of TDP-43 accumulate phosphorylated TDP-43 and rapidly convert into gels/solids in response to transient, arsenite-mediated stress. Cytoplasmic TDP-43 droplets slowly recruit importin-α and Nup62 and induce mislocalization of RanGap1, Ran, and Nup107, thereby provoking inhibition of nucleocytoplasmic transport, clearance of nuclear TDP-43, and cell death. These findings identify a neuronal cell death mechanism that can be initiated by transient-stress-induced cytosolic de-mixing of TDP-43.

| S-EPMC6548321 | biostudies-literature

Loss of nuclear TDP-43 in ALS causes altered expression of splicing machinery and widespread dysregulation of RNA splicing in motor neurons

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-06-01 | E-GEOD-56504 | biostudies-arrayexpress

TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes.

Project description:In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus. TDP-43 loss leads to cryptic exon inclusion but a role in other RNA processing events remains unresolved. Here, we show that loss of TDP-43 causes widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g., ELP1, NEFL, and TMEM106B) and providing evidence that alternative polyadenylation is a new facet of TDP-43 pathology.

| S-EPMC10849503 | biostudies-literature

Disrupted processing of long pre-mRNAs and widespread RNA missplicing are components of neuronal vulnerability from loss of nuclear TDP-43

Project description:This SuperSeries is composed of the SubSeries listed below.

2011-03-03 | GSE27394 | GEO