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Spliceosome integrity is defective in the motor neuron diseases ALS and SMA

Hitomi Tsuiji, Yohei Iguchi, Asako Furuya, Ayane Kataoka, Hiroyuki Hatsuta, Naoki Atsuta, Fumiaki Tanaka, Yoshio Hashizume, Hiroyasu Akatsu, Shigeo Murayama, Gen Sobue, Koji Yamanaka

Author Affiliations

  1. Hitomi Tsuiji (hitomitsuiji{at} *,1,
  2. Yohei Iguchi2,,
  3. Asako Furuya1,,
  4. Ayane Kataoka1,
  5. Hiroyuki Hatsuta3,
  6. Naoki Atsuta2,
  7. Fumiaki Tanaka2,
  8. Yoshio Hashizume4,
  9. Hiroyasu Akatsu5,
  10. Shigeo Murayama3,
  11. Gen Sobue2,6 and
  12. Koji Yamanaka (kyamanaka{at} *,1,6,7,8
  1. 1Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama, Japan
  2. 2Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
  3. 3Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi, Tokyo, Japan
  4. 4Department of Neuropathology, Fukushimura Hospital, Toyohashi, Aichi, Japan
  5. 5Choju Medical Institute, Fukushimura Hospital, Toyohashi, Aichi, Japan
  6. 6Japan Science and Technology Agency, CREST, Japan
  7. 7Brain Science Institute, Saitama University, Saitama, Japan
  8. 8Graduate School of Medicine, Kyoto University, Kyoto, Japan
  1. * Hitomi Tsuiji, Tel: +81 48 467 5467; Fax: +81 48 467 9725
    Koji Yamanaka, Tel: +81 48 467 9677; Fax: +81 48 467 9725
  1. These authors contributed equally to this work.

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Two motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are caused by distinct genes involved in RNA metabolism, TDP‐43 and FUS/TLS, and SMN, respectively. However, whether there is a shared defective mechanism in RNA metabolism common to these two diseases remains unclear. Here, we show that TDP‐43 and FUS/TLS localize in nuclear Gems through an association with SMN, and that all three proteins function in spliceosome maintenance. We also show that in ALS, Gems are lost, U snRNA levels are up‐regulated and spliceosomal U snRNPs abnormally and extensively accumulate in motor neuron nuclei, but not in the temporal lobe of FTLD with TDP‐43 pathology. This aberrant accumulation of U snRNAs in ALS motor neurons is in direct contrast to SMA motor neurons, which show reduced amounts of U snRNAs, while both have defects in the spliceosome. These findings indicate that a profound loss of spliceosome integrity is a critical mechanism common to neurodegeneration in ALS and SMA, and may explain cell‐type specific vulnerability of motor neurons.

  • Received November 28, 2012.
  • Revision received December 7, 2012.
  • Accepted December 7, 2012.
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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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