title: The extreme N-terminus of TDP-43 mediates the cytoplasmic aggregation of TDP-43 and associated toxicity in vivo.
abstract: Inclusions of Tar DNA- binding protein 43 (TDP-43) are a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP). Pathological TDP-43 exhibits the disease-specific biochemical signatures, which include its ubiquitination, phosphorylation and truncation. Recently, we demonstrated that the extreme N-terminus of TDP-43 regulates formation of abnormal cytoplasmic TDP-43 aggregation in cultured cells and primary neurons. However, it remained unclear whether this N-terminal domain mediates TDP-43 aggregation and the associated toxicity in vivo. To investigate this, we expressed a GFP-tagged TDP-43 with a nuclear localization signal mutation (GFP-TDP-43NLSm) and a truncated form without the extreme N-terminus (GFP-TDP-4310-414-NLSm) by adeno-associated viral (AAV) vectors in mouse primary cortical neurons and murine central nervous system. Compared to neurons containing GFP alone, expression of GFP-TDP-43NLSm resulted in the formation of ubiquitin-positive cytoplasmic inclusions and activation of caspase-3, an indicator of cell death. Moreover, mice expressing GFP-TDP-43NLSm proteins show reactive gliosis and develop neurological abnormalities. However, by deletion of TDP-43's extreme N-terminus, these pathological alterations can be abrogated. Together, our study provides further evidence confirming the critical role of the extreme N-terminus of TDP-43 in regulating protein structure as well as mediating toxicity associated with its aggregation. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasaguri
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA; Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chew
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Ya-Fei
authors.initials: YF
authors.lastname: Xu
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Aliesha
authors.initials: A
authors.lastname: Garrett
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Chris W
authors.initials: CW
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Jansen-West
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Peter O
authors.initials: PO
authors.lastname: Bauer
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Emilie A
authors.initials: EA
authors.lastname: Perkerson
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Jimei
authors.initials: J
authors.lastname: Tong
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Stetler
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Electronic address: Zhang.Yongjie@mayo.edu.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005911:Gliosis / Q000378:metabolism; D002479:Inclusion Bodies / Q000378:metabolism; D051379:Mice; D009043:Motor Activity; D009474:Neurons / Q000378:metabolism* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human; D053148:Caspase 3
keywords: AAV; Aggregation; In vivo; TDP-43; The extreme N-terminus; Toxicity