Accumulation of phosphorylated cytoplasmic TDP-43 inclusions accompanied by loss of normal nuclear TDP-43 in neurons and glia of the brain and spinal cord are the molecular hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the role of cytoplasmic TDP-43 in the pathogenesis of these neurodegenerative TDP-43 proteinopathies remains unclear, due in part to a lack of valid mouse models. We therefore generated new mice with doxycycline (Dox)-suppressible expression of human TDP-43 (hTDP-43) harboring a defective nuclear localization signal (∆NLS) under the control of the neurofilament heavy chain promoter. Expression of hTDP-43∆NLS in these ‘regulatable NLS’ (rNLS) mice resulted in the accumulation of insoluble, phosphorylated cytoplasmic TDP-43 in brain and spinal cord, loss of endogenous nuclear mouse TDP-43 (mTDP-43), brain atrophy, muscle denervation, dramatic motor neuron loss, and progressive motor impairments leading to death. Notably, suppression of hTDP-43∆NLS expression by return of Dox to rNLS mice after disease onset caused a dramatic decrease in phosphorylated TDP-43 pathology, an increase in nuclear mTDP-43 to control levels, and the prevention of further motor neuron loss. rNLS mice back on Dox also showed a significant increase in muscle innervation, a rescue of motor impairments, and a dramatic extension of lifespan. Thus, the rNLS mice are new TDP-43 mouse models that delineate the timeline of pathology development, muscle denervation and neuron loss in ALS/FTLD-TDP. Importantly, even after neurodegeneration and onset of motor dysfunction, removal of cytoplasmic TDP-43 and the concomitant return of nuclear TDP-43 led to neuron preservation, muscle re-innervation and functional recovery.
Amyotrophic lateral sclerosis (ALS) Frontotemporal dementia (FTD) Frontotemporal lobar degeneration (FTLD) TDP-43 Neurodegeneration Motor neuron Spinal cord Mouse model
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We thank Drs. Todd Cohen, Edward B. Lee, Sílvia Porta and Kurt Brunden for helpful discussion and input on the manuscript, Chi Li and Clark Restrepo for technical assistance, Drs. Manuela Neumann and Elizabeth Kremmer for providing the phosphorylation specific TDP-43 rat monoclonal antibody TAR5P-1D3, Dr. Xu-Gang Xia, Thomas Jefferson University for the NEFH-tTA construct, Dr. Chris Henderson, Columbia University for the VAChT antibody, and Dr. Jean Richa of the University of Pennsylvania Transgenic and Chimeric Mouse Facility for transgenic mouse production. This work was supported by NIH/NIA AG032953 and AG17586, and by Australian National Health & Medical Research Council C.J. Martin Biomedical Early Career Fellowship 1036835 (to A.W.).
Compliance with ethical standards
Conflict of interest
The authors declare no competing financial interests.
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.
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