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PABPN1 suppresses TDP-43 toxicity in ALS disease models.

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.
AuthorsChing-Chieh Chou, Olga M Alexeeva, Shizuka Yamada, Amy Pribadi, Yi Zhang, Bi Mo, Kathryn R Williams, Daniela C Zarnescu, Wilfried Rossoll
JournalHuman molecular genetics (Hum Mol Genet) Vol. 24 Issue 18 Pg. 5154-73 (Sep 15 2015) ISSN: 1460-2083 [Electronic] England
PMID26130692 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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
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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