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PARP-1 activation leads to cytosolic accumulation of TDP-43 in neurons.
- Source :
-
Neurochemistry international [Neurochem Int] 2021 Sep; Vol. 148, pp. 105077. Date of Electronic Publication: 2021 May 31. - Publication Year :
- 2021
-
Abstract
- Oxidative stress in neurodegenerative disease leads to poly(ADP-ribose) polymerase 1 (PARP-1) overactivation and subsequent cell death via excessive generation of Poly(ADP-ribose) polymer (PAR). PAR binds to neurodegenerative disease linked protein TAR DNA binding protein of 43 kDa (TDP-43). However, the consequence of this interaction is not yet fully understood. TDP-43 translocates from the nucleus to the cytoplasm in response to oxidative stress, but the mechanism of stress-induced translocation remains unknown. We used N-methyl-N-nitroso-N'-nitroguanidine (MNNG) and oxygen-glucose deprivation (OGD) in mouse neuronal cultures to activate PARP-1 and observed that pharmacological inhibition of PARP-1 blocked the cytosolic translocation of TDP-43. PARP-1 inhibition is also neuroprotective against both MNNG and OGD, suggesting that PARP inhibitors could play a role in the neuroprotective role in neurodegenerative diseases involving TDP-43. Together, these data present the novel finding that TDP-43 translocation depends on PARP-1 activation and set a ground for future research of how PARP-1 activation or PAR binding to TDP-43 may facilitate its cytosolic accumulation.<br /> (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Cell Death drug effects
Cell Death genetics
Cells, Cultured
DNA-Binding Proteins genetics
Enzyme Activation
Female
Glucose deficiency
Hypoxia metabolism
Methylnitronitrosoguanidine pharmacology
Mice
Neuroprotective Agents pharmacology
Oxidative Stress
Poly (ADP-Ribose) Polymerase-1 antagonists & inhibitors
Poly (ADP-Ribose) Polymerase-1 genetics
Pregnancy
Primary Cell Culture
Translocation, Genetic
Cytosol metabolism
DNA-Binding Proteins biosynthesis
Neurons metabolism
Poly (ADP-Ribose) Polymerase-1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1872-9754
- Volume :
- 148
- Database :
- MEDLINE
- Journal :
- Neurochemistry international
- Publication Type :
- Academic Journal
- Accession number :
- 34082062
- Full Text :
- https://doi.org/10.1016/j.neuint.2021.105077