Loss of TDP-43 causes age-dependent progressive motor neuron degeneration

Yohei Iguchi, Masahisa Katsuno, Jun Ichi Niwa, Shinnosuke Takagi, Shinsuke Ishigaki, Kensuke Ikenaka, Kaori Kawai, Hirohisa Watanabe, Koji Yamanaka, Ryosuke Takahashi, Hidemi Misawa, Shoichi Sasaki, Fumiaki Tanaka, Gen Sobue

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis is a devastating, progressive neurodegenerative disease that affects upper and lower motor neurons. Although several genes are identified as the cause of familial cases, the pathogeneses of sporadic forms, which account for 90% of amyotrophic lateral sclerosis, have not been elucidated. Transactive response DNA-binding protein 43 a nuclear protein regulating RNA processing, redistributes to the cytoplasm and forms aggregates, which are the histopathological hallmark of sporadic amyotrophic lateral sclerosis, in affected motor neurons, suggesting that loss-of-function of transactive response DNA-binding protein 43 is one of the causes of the neurodegeneration. To test this hypothesis, we assessed the effects of knockout of transactive response DNA-binding protein 43 in mouse postnatal motor neurons using Cre/loxp system. These mice developed progressive weight loss and motor impairment around the age of 60 weeks, and exhibited degeneration of large motor axon, grouped atrophy of the skeletal muscle, and denervation in the neuromuscular junction. The spinal motor neurons lacking transactive response DNA-binding protein 43 were not affected for 1 year, but exhibited atrophy at the age of 100 weeks; whereas, extraocular motor neurons, that are essentially resistant in amyotrophic lateral sclerosis, remained preserved even at the age of 100 weeks. Additionally, ultra structural analysis revealed autolysosomes and autophagosomes in the cell bodies and axons of motor neurons of the 100-week-old knockout mice. In summary, the mice in which transactive response DNA-binding protein 43 was knocked-out specifically in postnatal motor neurons exhibited an age-dependent progressive motor dysfunction accompanied by neuropathological alterations, which are common to sporadic amyotrophic lateral sclerosis. These findings suggest that transactive response DNA-binding protein 43 plays an essential role in the long term maintenance of motor neurons and that loss-of-function of this protein seems to contribute to the pathogenesis of amyotrophic lateral sclerosis.

Original languageEnglish
Pages (from-to)1371-1382
Number of pages12
JournalBrain
Volume136
Issue number5
DOIs
Publication statusPublished - 2013 May

Fingerprint

Nerve Degeneration
Motor Neurons
DNA-Binding Proteins
Amyotrophic Lateral Sclerosis
Atrophy
Axons
Muscle Denervation
Causes
Degeneration
Neuron
Neuromuscular Junction
Nuclear Proteins
Knockout Mice
Neurodegenerative Diseases
Weight Loss
Protein
Cytoplasm
Skeletal Muscle
RNA

Keywords

  • amyotrophic lateral sclerosis
  • autophagosome
  • axonal degeneration
  • transactive response DNA-binding protein 43

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Iguchi, Y., Katsuno, M., Niwa, J. I., Takagi, S., Ishigaki, S., Ikenaka, K., ... Sobue, G. (2013). Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain, 136(5), 1371-1382. https://doi.org/10.1093/brain/awt029

Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. / Iguchi, Yohei; Katsuno, Masahisa; Niwa, Jun Ichi; Takagi, Shinnosuke; Ishigaki, Shinsuke; Ikenaka, Kensuke; Kawai, Kaori; Watanabe, Hirohisa; Yamanaka, Koji; Takahashi, Ryosuke; Misawa, Hidemi; Sasaki, Shoichi; Tanaka, Fumiaki; Sobue, Gen.

In: Brain, Vol. 136, No. 5, 05.2013, p. 1371-1382.

Research output: Contribution to journalArticle

Iguchi, Y, Katsuno, M, Niwa, JI, Takagi, S, Ishigaki, S, Ikenaka, K, Kawai, K, Watanabe, H, Yamanaka, K, Takahashi, R, Misawa, H, Sasaki, S, Tanaka, F & Sobue, G 2013, 'Loss of TDP-43 causes age-dependent progressive motor neuron degeneration', Brain, vol. 136, no. 5, pp. 1371-1382. https://doi.org/10.1093/brain/awt029
Iguchi Y, Katsuno M, Niwa JI, Takagi S, Ishigaki S, Ikenaka K et al. Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain. 2013 May;136(5):1371-1382. https://doi.org/10.1093/brain/awt029
Iguchi, Yohei ; Katsuno, Masahisa ; Niwa, Jun Ichi ; Takagi, Shinnosuke ; Ishigaki, Shinsuke ; Ikenaka, Kensuke ; Kawai, Kaori ; Watanabe, Hirohisa ; Yamanaka, Koji ; Takahashi, Ryosuke ; Misawa, Hidemi ; Sasaki, Shoichi ; Tanaka, Fumiaki ; Sobue, Gen. / Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. In: Brain. 2013 ; Vol. 136, No. 5. pp. 1371-1382.
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