title: 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.
authors.affiliation: Department of Cell Biology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Ching-Chieh
authors.initials: CC
authors.lastname: Chou
authors.affiliation: Department of Cell Biology.
authors.forename: Olga M
authors.initials: OM
authors.lastname: Alexeeva
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA and.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA and.
authors.forename: Amy
authors.initials: A
authors.lastname: Pribadi
authors.affiliation: Department of Cell Biology, Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology.
authors.forename: Bi
authors.initials: B
authors.lastname: Mo
authors.affiliation: Department of Cell Biology.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Williams
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA and.
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Zarnescu
authors.affiliation: Department of Cell Biology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA, wrossol@emory.edu.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Rossoll
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D039122:Poly(A)-Binding Protein I / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods; D021381:Protein Transport; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C576588:PABPN1 protein, human; D039122:Poly(A)-Binding Protein I; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex