title: Loss of TDP-43 causes age-dependent progressive motor neuron degeneration.
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.
authors: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors: Yohei
authors: Y
authors: Iguchi
authors: Masahisa
authors: M
authors: Katsuno
authors: Jun-ichi
authors: J
authors: Niwa
authors: Shinnosuke
authors: S
authors: Takagi
authors: Shinsuke
authors: S
authors: Ishigaki
authors: Kensuke
authors: K
authors: Ikenaka
authors: Kaori
authors: K
authors: Kawai
authors: Hirohisa
authors: H
authors: Watanabe
authors: Koji
authors: K
authors: Yamanaka
authors: Ryosuke
authors: R
authors: Takahashi
authors: Hidemi
authors: H
authors: Misawa
authors: Shoichi
authors: S
authors: Sasaki
authors: Fumiaki
authors: F
authors: Tanaka
authors: Gen
authors: G
authors: Sobue
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D004268:DNA-Binding Proteins; C578077:Tardbp protein, mouse