title: Nucleus Accumbens 1, a Pox virus and Zinc finger/Bric-a-brac Tramtrack Broad protein binds to TAR DNA-binding protein 43 and has a potential role in Amyotrophic Lateral Sclerosis.
abstract: Protein degradation is a critical component of cellular maintenance. The intracellular translocation and targeting of the Ubiquitin Proteasome System (UPS) differentially coordinates a protein's half-life and thereby its function. Nucleus Accumbens 1 (NAC1), a member of the Pox virus and Zinc finger/Bric-a-brac Tramtrack Broad complex (POZ/BTB) family of proteins, participates in the coordinated proteolysis of synaptic proteins by mediating recruitment of the UPS to dendritic spines. Here we report a novel interaction between NAC1 and TAR DNA-binding protein 43 (TDP-43), a protein identified as the primary component of ubiquitinated protein aggregates found in patients with Amyotrophic Lateral Sclerosis (ALS). In vitro translated full-length TDP-43 associated with both the POZ/BTB domain and the non-POZ/BTB domain of NAC1 in GST pulldown assays. Other POZ/BTB proteins (including zinc finger POZ/BTB proteins and atypical POZ/BTB proteins) showed weak interactions with TDP-43. In addition, NAC1 and TDP-43 were present in the same immunocomplexes in different regions of mouse brain and spinal cord. In primary spinal cord cultures, TDP-43 expression was mainly nuclear, whereas NAC1 was both nuclear and cytoplasmic. In order to mimic ALS-like toxicity in the spinal cord culture system, we elevated extracellular glutamate levels resulting in the selective loss of motor neurons. Using this model, it was found that glutamate toxicity elicited a dose-dependent translocation of TDP-43 out of the nucleus of cholinergic neurons and increased the co-localization of NAC1 and TDP-43. These findings suggest that NAC1 may function to link TDP-43 to the proteasome; thereby, facilitating the post-translational modifications of TDP-43 that lead to the development of ALS.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA. scofield@musc.edu
authors.forename: M D
authors.initials: MD
authors.lastname: Scofield
authors.forename: L
authors.initials: L
authors.lastname: Korutla
authors.forename: T G
authors.initials: TG
authors.lastname: Jackson
authors.forename: P W
authors.initials: PW
authors.lastname: Kalivas
authors.forename: S A
authors.initials: SA
authors.lastname: Mackler
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D047468:Immunoprecipitation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology; D014162:Transfection; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; C516477:NACC1 protein, human; D009363:Neoplasm Proteins; D012097:Repressor Proteins; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; D002795:Choline O-Acetyltransferase; D010751:Phosphopyruvate Hydratase