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Hum Mol Genet. 2015 Sep 15;24(18):5154-73. doi: 10.1093/hmg/ddv238. Epub 2015 Jun 30.

PABPN1 suppresses TDP-43 toxicity in ALS disease models.

Author information

1
Department of Cell Biology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA.
2
Department of Cell Biology.
3
Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA and.
4
Department of Cell Biology, Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
5
Department of Cell Biology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA, wrossol@emory.edu.

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.

PMID:
26130692
PMCID:
PMC4550816
DOI:
10.1093/hmg/ddv238
[Indexed for MEDLINE]
Free PMC Article

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