title: Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice.
abstract: Transactivation response DNA-binding protein 43 (TDP-43) is a principal component of ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations. While TDP-43 has been ascribed a number of roles in normal biology, including mRNA splicing and transcription regulation, elucidating disease mechanisms associated with this protein is hindered by the lack of models to dissect such functions. We have generated transgenic (TDP-43PrP) mice expressing full-length human TDP-43 (hTDP-43) driven by the mouse prion promoter to provide a tool to analyze the role of wild-type hTDP-43 in the brain and spinal cord. Expression of hTDP-43 caused a dose-dependent downregulation of mouse TDP-43 RNA and protein. Moderate overexpression of hTDP-43 resulted in TDP-43 truncation, increased cytoplasmic and nuclear ubiquitin levels, and intranuclear and cytoplasmic aggregates that were immunopositive for phosphorylated TDP-43. Of note, abnormal juxtanuclear aggregates of mitochondria were observed, accompanied by enhanced levels of Fis1 and phosphorylated DLP1, key components of the mitochondrial fission machinery. Conversely, a marked reduction in mitofusin 1 expression, which plays an essential role in mitochondrial fusion, was observed in TDP-43PrP mice. Finally, TDP-43PrP mice showed reactive gliosis, axonal and myelin degeneration, gait abnormalities, and early lethality. This TDP-43 transgenic line provides a valuable tool for identifying potential roles of wild-type TDP-43 within the CNS and for studying TDP-43-associated neurotoxicity.
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors: Ya-Fei
authors: YF
authors: Xu
authors: Tania F
authors: TF
authors: Gendron
authors: Yong-Jie
authors: YJ
authors: Zhang
authors: Wen-Lang
authors: WL
authors: Lin
authors: Simon
authors: S
authors: D'Alton
authors: Hong
authors: H
authors: Sheng
authors: Monica Castanedes
authors: MC
authors: Casey
authors: Jimei
authors: J
authors: Tong
authors: Joshua
authors: J
authors: Knight
authors: Xin
authors: X
authors: Yu
authors: Rosa
authors: R
authors: Rademakers
authors: Kevin
authors: K
authors: Boylan
authors: Mike
authors: M
authors: Hutton
authors: Eileen
authors: E
authors: McGowan
authors: Dennis W
authors: DW
authors: Dickson
authors: Jada
authors: J
authors: Lewis
authors: Leonard
authors: L
authors: Petrucelli
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009069:Movement Disorders / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000401:mortality / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D011328:Prions / Q000235:genetics / Q000378:metabolism; D016622:Silver Staining / Q000379:methods; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure
chemical_list: D004268:DNA-Binding Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D011328:Prions; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C110768:DNM1L protein, human; D034281:Dynamins