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Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats
Cao Huang, … , Hongxia Zhou, Xu-Gang Xia
Cao Huang, … , Hongxia Zhou, Xu-Gang Xia
Published December 12, 2011
Citation Information: J Clin Invest. 2012;122(1):107-118. https://doi.org/10.1172/JCI59130.
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Research Article Neuroscience

Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats

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Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration, which ultimately leads to paralysis and death. Mutation of TAR DNA binding protein 43 (TDP-43) has been linked to the development of an inherited form of ALS. Existing TDP-43 transgenic animals develop a limited loss of motor neurons and therefore do not faithfully reproduce the core phenotype of ALS. Here, we report the creation of multiple lines of transgenic rats in which expression of ALS-associated mutant human TDP-43 is restricted to either motor neurons or other types of neurons and skeletal muscle and can be switched on and off. All of these rats developed progressive paralysis reminiscent of ALS when the transgene was switched on. Rats expressing mutant TDP-43 in motor neurons alone lost more spinal motor neurons than rats expressing the disease gene in varying neurons and muscle cells, although these rats all developed remarkable denervation atrophy of skeletal muscles. Intriguingly, progression of the disease was halted after transgene expression was switched off; in rats with limited loss of motor neurons, we observed a dramatic recovery of motor function, but in rats with profound loss of motor neurons, we only observed a moderate recovery of motor function. Our finding suggests that mutant TDP-43 in motor neurons is sufficient to promote the onset and progression of ALS and that motor neuron degeneration is partially reversible, at least in mutant TDP-43 transgenic rats.

Authors

Cao Huang, Jianbin Tong, Fangfang Bi, Hongxia Zhou, Xu-Gang Xia

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Figure 1

Restricted overexpression of mutant human TDP-43 (hTDP-43) in neurons is achieved in rats.

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Restricted overexpression of mutant human TDP-43 (hTDP-43) in neurons is...
(A) Immunoblotting showed that the hTDP-43 transgene was expressed in the spinal cord (SP) and hippocampus (HP) of NEF-tTA/TRE–TDP-43M337V double-transgenic rats soon after Dox was withdrawn (Dox–). The rats were deprived of Dox at the age of 60 days. Equal loading was confirmed by probing the same membrane with an antibody to GAPDH. (B–J) Human TDP-43 immunoreactivity was examined in the spinal cord (B–D), cortex (E–H), and hippocampus (I and J) of NEF-tTA/TRE–TDP-43M337V double-transgenic (C, D, and G–J) and NEF-tTA single-transgenic (B, E, and F) rats. Coronal sections of neocortex were counterstained lightly with hematoxylin to display the nuclei (E–H). (K–P) Double-label fluorescence staining revealed that human TDP-43 (green, K, M, N, and P) was colocalized with the neuronal marker NeuN (red, L and M), but was not colocalized with the astrocyte marker GFAP (red: O and P) in the cortex. Rats were examined 10 days after Dox withdrawal. Scale bars: 200 μm (B, C, and I); 100 μm (E and G); 20 μm (D, F, H, and J–P).

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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