TDP43 autoregulation gives rise to shortened isoforms that are tightly controlled by both transcriptional and post-translational mechanisms DOI
Megan M. Dykstra, Kaitlin Weskamp, Nicolás Gómez

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 4, 2024

Abstract The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal isoforms that are predominantly cytosolic localization, highly prone to aggregation, enriched susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 difficult detect comparison full-length (fl)TDP43, raising questions regarding their origin selective regulation. Here, we show sTDP43 created as a byproduct autoregulation cleared by nonsense mediated RNA decay (NMD). sTDP43-encoding transcripts escape NMD can lead toxicity but rapidly degraded post-translationally. Circumventing regulatory mechanisms overexpressing results neurodegeneration vitro vivo via oligomerization impairment flTDP43 splicing activity, addition binding-dependent gain-of-function toxicity. Collectively, highlight endogenous tightly regulate expression provide insight into consequences aberrant accumulation disease.

Language: Английский

TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms DOI Creative Commons
Megan M. Dykstra, Kaitlin Weskamp, Nicolás Gómez

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(1), P. 115113 - 115113

Published: Jan. 1, 2025

Highlights•Short (s)TDP43 isoforms are created as a by-product of TDP43 autoregulation•sTDP43 is strictly regulated by NMD, the proteasome, and autophagy•sTDP43 potent inhibitor splicing activitySummaryThe nuclear RNA-binding protein integrally involved in pathogenesis amyotrophic lateral sclerosis (ALS) frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal that predominantly cytosolic localization, prone to aggregation, enriched susceptible spinal motor neurons. In healthy cells, however, these shortened difficult detect comparison full-length (fl)TDP43, raising questions regarding their origin selective regulation. Here, we show sTDP43 autoregulation cleared nonsense-mediated RNA decay (NMD). sTDP43-encoding transcripts escape NMD rapidly degraded post-translationally via proteasome macroautophagy. Circumventing regulatory mechanisms overexpressing results neurodegeneration oligomerization impairment flTDP43 activity, addition RNA-binding-dependent gain-of-function toxicity. Collectively, highlight endogenous tightly regulate expression underscore consequences aberrant accumulation disease.Graphical abstract

Language: Английский

Citations

1
An ANXA11 P93S variant dysregulates TDP‐43 and causes corticobasal syndrome DOI Creative Commons
Allison Snyder, Veronica H. Ryan, James Hawrot

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(8), P. 5220 - 5235

Published: June 26, 2024

Abstract INTRODUCTION Variants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity a novel VUS P93S in Annexin A11 (ANXA11) – an amyotrophic lateral sclerosis/frontotemporal dementia‐associated gene corticobasal syndrome kindred. Established ANXA11 mutations cause aggregation, altered lysosomal‐RNA granule co‐trafficking, and transactive response DNA binding protein 43 kDa (TDP‐43) mis‐localization. METHODS described clinical presentation explored phenotypic diversity variants. P93S's effect on function TDP‐43 biology was characterized induced pluripotent stem cell‐derived neurons alongside multiomic neuronal microglial profiling. RESULTS were linked to cases. led decreased lysosome colocalization, neuritic RNA, nuclear cryptic exon expression. Multiomic signatures implicated immune dysregulation interferon signaling pathways. DISCUSSION This study establishes pathogenicity, broadens spectrum mutations, underscores dysfunction pathophysiology, demonstrates potential cellular models determine variant Highlights is pathogenic variant. Corticobasal part spectrum. Hybridization chain reaction fluorescence situ hybridization (HCR FISH) new tool detection exons due TDP‐43‐related loss splicing regulation. Microglial related pathways are important drivers disease. Cellular powerful tools adjudicating variants significance.

Language: Английский

Citations

3
TDP43 autoregulation gives rise to shortened isoforms that are tightly controlled by both transcriptional and post-translational mechanisms DOI
Megan M. Dykstra, Kaitlin Weskamp, Nicolás Gómez

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 4, 2024

Abstract The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal isoforms that are predominantly cytosolic localization, highly prone to aggregation, enriched susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 difficult detect comparison full-length (fl)TDP43, raising questions regarding their origin selective regulation. Here, we show sTDP43 created as a byproduct autoregulation cleared by nonsense mediated RNA decay (NMD). sTDP43-encoding transcripts escape NMD can lead toxicity but rapidly degraded post-translationally. Circumventing regulatory mechanisms overexpressing results neurodegeneration vitro vivo via oligomerization impairment flTDP43 splicing activity, addition binding-dependent gain-of-function toxicity. Collectively, highlight endogenous tightly regulate expression provide insight into consequences aberrant accumulation disease.

Language: Английский

Citations

0