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Acta Neuropathol Commun. 2015 Jun 25;3:36. doi: 10.1186/s40478-015-0212-4.

Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS.

Author information

1
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.
2
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.
3
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.
4
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.
5
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.
6
Centre for Ultrastructural Imaging, Kings College London, London, SE1 1UL, UK. leanne.glover@kcl.ac.uk.
7
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.
8
Ludwig Institute for Cancer Research and Department of Molecular Medicine, University of California at San Diego, La Jolla, CA, 92093, USA. ejsun@ucsd.edu.
9
Present address: Neurogenetics Branch, NINDS, National Institutes of Health, Bethesda, MD, 20892, USA. ejsun@ucsd.edu.
10
Ludwig Institute for Cancer Research and Department of Molecular Medicine, University of California at San Diego, La Jolla, CA, 92093, USA. sling@ucsd.edu.
11
Ludwig Institute for Cancer Research and Department of Molecular Medicine, University of California at San Diego, La Jolla, CA, 92093, USA. mmcalonis@ucsd.edu.
12
Ludwig Institute for Cancer Research and Department of Molecular Medicine, University of California at San Diego, La Jolla, CA, 92093, USA. sdacruz@ucsd.edu.
13
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.
14
Present address: Institute of Molecular Life Sciences, University of Zurich, Zurich, CH-8057, Switzerland. magdalini.polymenidou@imls.uzh.ch.
15
Mouse Cancer Genetics Program, National Cancer Institute - Frederick, Frederick, MD, 21702, USA. tessarol@mail.nih.gov.
16
Ludwig Institute for Cancer Research and Department of Molecular Medicine, University of California at San Diego, La Jolla, CA, 92093, USA. dcleveland@ucsd.edu.
17
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.

Abstract

INTRODUCTION:

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.

PMID:
26108367
PMCID:
PMC4479086
DOI:
10.1186/s40478-015-0212-4
[Indexed for MEDLINE]
Free PMC Article

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