Abstract |
TAR DNA-binding protein 43 (TDP-43) is a major disease protein in amyotrophic lateral sclerosis (ALS) and related neurodegenerative diseases. Both the cytoplasmic accumulation of toxic ubiquitinated and hyperphosphorylated TDP-43 fragments and the loss of normal TDP-43 from the nucleus may contribute to the disease progression by impairing normal RNA and protein homeostasis. Therefore, both the removal of pathological protein and the rescue of TDP-43 mislocalization may be critical for halting or reversing TDP-43 proteinopathies. Here, we report poly(A)-binding protein nuclear 1 (PABPN1) as a novel TDP-43 interaction partner that acts as a potent suppressor of TDP-43 toxicity. Overexpression of full-length PABPN1 but not a truncated version lacking the nuclear localization signal protects from pathogenic TDP-43-mediated toxicity, promotes the degradation of pathological TDP-43 and restores normal solubility and nuclear localization of endogenous TDP-43. Reduced levels of PABPN1 enhances the phenotypes in several cell culture and Drosophila models of ALS and results in the cytoplasmic mislocalization of TDP-43. Moreover, PABPN1 rescues the dysregulated stress granule (SG) dynamics and facilitates the removal of persistent SGs in TDP-43-mediated disease conditions. These findings demonstrate a role for PABPN1 in rescuing several cytopathological features of TDP-43 proteinopathy by increasing the turnover of pathologic proteins.
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Authors | Ching-Chieh Chou, Olga M Alexeeva, Shizuka Yamada, Amy Pribadi, Yi Zhang, Bi Mo, Kathryn R Williams, Daniela C Zarnescu, Wilfried Rossoll |
Journal | Human molecular genetics
(Hum Mol Genet)
Vol. 24
Issue 18
Pg. 5154-73
(Sep 15 2015)
ISSN: 1460-2083 [Electronic] England |
PMID | 26130692
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]. |
Chemical References |
- Carrier Proteins
- DNA-Binding Proteins
- PABPN1 protein, human
- Poly(A)-Binding Protein I
- Ubiquitin
- Proteasome Endopeptidase Complex
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Topics |
- Amyotrophic Lateral Sclerosis
(genetics, metabolism, pathology)
- Animals
- Brain
(metabolism, pathology)
- Carrier Proteins
(metabolism)
- Cell Line, Tumor
- Cell Nucleus
(metabolism)
- DNA-Binding Proteins
(genetics, metabolism)
- Disease Models, Animal
- Drosophila
(genetics, metabolism)
- Gene Expression
- Humans
- Mice
- Mutation
- Neurons
(metabolism)
- Poly(A)-Binding Protein I
(genetics, metabolism)
- Proteasome Endopeptidase Complex
(metabolism)
- Protein Aggregation, Pathological
- Protein Binding
- Protein Interaction Mapping
(methods)
- Protein Transport
- TDP-43 Proteinopathies
(genetics, metabolism, pathology)
- Two-Hybrid System Techniques
- Ubiquitin
(metabolism)
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