Details

Autor(en) / Beteiligte

• Lee, Youn-Bok
• Scotter, Emma L
• Lee, Do-Young
• Troakes, Claire
• Mitchell, Jacqueline
• Rogelj, Boris
• Gallo, Jean-Marc
• Shaw, Christopher E

Titel

Cytoplasmic TDP-43 is involved in cell fate during stress recovery

Ist Teil von

• Human molecular genetics, 2021-12, Vol.31 (2), p.166-175

Ort / Verlag

England: Oxford University Press

Erscheinungsjahr

2021

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• Abstract Transactive response DNA binding protein 43 (TDP-43) is an RNA processing protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Nuclear TDP-43 mislocalizes in patients to the cytoplasm, where it forms ubiquitin-positive inclusions in affected neurons and glia. Physiologically, cytoplasmic TDP-43 is associated with stress granules (SGs). Here, we explored TDP-43 cytoplasmic accumulation and stress granule formation following osmotic and oxidative stress. We show that sorbitol drives TDP-43 redistribution to the cytoplasm, while arsenite induces the recruitment of cytoplasmic TDP-43 to TIA-1 positive SGs. We demonstrate that inducing acute oxidative stress after TDP-43 cytoplasmic relocalization by osmotic shock induces poly (ADP-ribose) polymerase (PARP) cleavage, which triggers cellular toxicity. Recruitment of cytoplasmic TDP-43 to polyribosomes occurs in an SH-SY5Y cellular stress model and is observed in FTD brain lysate. Moreover, the processing body (P-body) marker DCP1a is detected in TDP-43 granules during recovery from stress. Overall, this study supports a central role for cytoplasmic TDP-43 in controlling protein translation in stressed cells.