title: Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder, and cytoplasmic inclusions containing transactive response (TAR) DNA binding protein (TDP-43) are present in ~90 % of cases. Here we report detailed pathology in human TDP-43 transgenic mice that recapitulate key features of TDP-43-linked ALS.
  
  
  RESULTS
  Expression of human wild-type TDP-43 (TDP-43(WT)) caused no clinical or pathological phenotype, while expression of Q331K mutant (TDP-43(Q331K)) resulted in a non-lethal age-dependent motor phenotype, accompanied by cytoplasmic TDP-43 aggregation, mild neuronal loss, with astroglial and microglial activation in the motor cortex and spinal cord at 24 months. However, co-expression of WT and Q331K mutant (TDP-43(WTxQ331K)) resulted in an extremely aggressive motor phenotype with tremor from 3 weeks and progressive hind-limb paralysis necessitating euthanasia by 8-10 weeks of age. Neuronal loss and reactive gliosis was observed in the spinal cord and layer V region of the cortex, with TDP-43, ubiquitin and p62 cytoplasmic inclusions and an increase in insoluble TDP-43. Nuclear clearance of TDP-43 was not observed in TDP-43(Q331K) mice but was seen in 65 % of aggregate containing spinal cord motor neurons in TDP-43(WTxQ331K) mice.
  
  
  CONCLUSIONS
  We hypothesise that cytoplasmic TDP-43(Q331K) aggregates facilitate the recruitment of WT protein in compound animals, which dramatically accelerates neurodegeneration and disease progression. The exploration of disease mechanisms in slow and rapid disease models of TDP-43 proteinopathy will help elucidate novel drug targets and provide a more informative platform for preclinical trials.
authors.affiliation: King's Centre for Neurodegeneration Research, Kings College London, Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, London, SE5 8AF, UK. jacqueline.mitchell@kcl.ac.uk.
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Mitchell
authors.affiliation: King's Centre for Neurodegeneration Research, Kings College London, Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, London, SE5 8AF, UK. remy.constable@kcl.ac.uk.
authors.forename: Remy
authors.initials: R
authors.lastname: Constable
authors.affiliation: King's Centre for Neurodegeneration Research, Kings College London, Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, London, SE5 8AF, UK. eva.so@kcl.ac.uk.
authors.forename: Eva
authors.initials: E
authors.lastname: So
authors.affiliation: King's Centre for Neurodegeneration Research, Kings College London, Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, London, SE5 8AF, UK. caroline.vance@kcl.ac.uk.
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.affiliation: King's Centre for Neurodegeneration Research, Kings College London, Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, London, SE5 8AF, UK. emma.scotter@kcl.ac.uk.
authors.forename: Emma
authors.initials: E
authors.lastname: Scotter
authors.affiliation: Centre for Ultrastructural Imaging, Kings College London, London, SE1 1UL, UK. leanne.glover@kcl.ac.uk.
authors.forename: Leanne
authors.initials: L
authors.lastname: Glover
authors.affiliation: King's Centre for Neurodegeneration Research, Kings College London, Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, London, SE5 8AF, UK. tibor.hortobagyi@kcl.ac.uk.
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobagyi
authors.affiliation: Ludwig Institute for Cancer Research and Department of Molecular Medicine, University of California at San Diego, La Jolla, CA, 92093, USA. ejsun@ucsd.edu.|Present address: Neurogenetics Branch, NINDS, National Institutes of Health, Bethesda, MD, 20892, USA. ejsun@ucsd.edu.
authors.forename: Eveline S
authors.initials: ES
authors.lastname: Arnold
authors.affiliation: Ludwig Institute for Cancer Research and Department of Molecular Medicine, University of California at San Diego, La Jolla, CA, 92093, USA. sling@ucsd.edu.
authors.forename: Shuo-Chien
authors.initials: SC
authors.lastname: Ling
authors.affiliation: Ludwig Institute for Cancer Research and Department of Molecular Medicine, University of California at San Diego, La Jolla, CA, 92093, USA. mmcalonis@ucsd.edu.
authors.forename: Melissa
authors.initials: M
authors.lastname: McAlonis
authors.affiliation: Ludwig Institute for Cancer Research and Department of Molecular Medicine, University of California at San Diego, La Jolla, CA, 92093, USA. sdacruz@ucsd.edu.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Da Cruz
authors.affiliation: Ludwig Institute for Cancer Research and Department of Molecular Medicine, University of California at San Diego, La Jolla, CA, 92093, USA. magdalini.polymenidou@imls.uzh.ch.|Present address: Institute of Molecular Life Sciences, University of Zurich, Zurich, CH-8057, Switzerland. magdalini.polymenidou@imls.uzh.ch.
authors.forename: Magda
authors.initials: M
authors.lastname: Polymenidou
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute - Frederick, Frederick, MD, 21702, USA. tessarol@mail.nih.gov.
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarolo
authors.affiliation: Ludwig Institute for Cancer Research and Department of Molecular Medicine, University of California at San Diego, La Jolla, CA, 92093, USA. dcleveland@ucsd.edu.
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.affiliation: King's Centre for Neurodegeneration Research, Kings College London, Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, London, SE5 8AF, UK. christopher.shaw@kcl.ac.uk.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002540:Cerebral Cortex / Q000473:pathology*; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D013116:Spinal Cord / Q000473:pathology
chemical_list: D015703:Antigens, CD; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C000598624:TARDBP protein, human