CLP1 links tRNA metabolism to progressive motor-neuron loss

Toshikatsu Hanada, Stefan Weitzer, Barbara Mair, Christian Bernreuther, Brian J. Wainger, Justin Ichida, Reiko Hanada, Michael Orthofer, Shane J. Cronin, Vukoslav Komnenovic, Adi Minis, Fuminori Sato, Hiromitsu Mimata, Akihiko Yoshimura, Ido Tamir, Johannes Rainer, Reinhard Kofler, Avraham Yaron, Kevin C. Eggan, Clifford J. Woolf, Markus Glatzel, Ruth Herbst, Javier Martinez () and Josef M. Penninger ()
Additional contact information
Toshikatsu Hanada: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria
Stefan Weitzer: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria
Barbara Mair: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria
Christian Bernreuther: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany
Brian J. Wainger: Program in Neurobiology and F. M. Kirby Neurobiology Center, Boston Children’s Hospital
Justin Ichida: Howard Hughes Medical Institute, Harvard Stem Cell Institute. Boston
Reiko Hanada: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria
Michael Orthofer: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria
Shane J. Cronin: Program in Neurobiology and F. M. Kirby Neurobiology Center, Boston Children’s Hospital
Vukoslav Komnenovic: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria
Adi Minis: Rehovot 76100, Israel
Fuminori Sato: Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan
Hiromitsu Mimata: Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan
Akihiko Yoshimura: Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
Ido Tamir: Campus Science Support Facilities GmbH, Dr. Bohr-Gasse 3, Vienna 1030, Austria
Johannes Rainer: Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria
Reinhard Kofler: Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria
Avraham Yaron: Rehovot 76100, Israel
Kevin C. Eggan: Howard Hughes Medical Institute, Harvard Stem Cell Institute. Boston
Clifford J. Woolf: Program in Neurobiology and F. M. Kirby Neurobiology Center, Boston Children’s Hospital
Markus Glatzel: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany
Ruth Herbst: Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna 1090, Austria
Javier Martinez: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria
Josef M. Penninger: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria

Nature, 2013, vol. 495, issue 7442, 474-480

Abstract: Abstract CLP1 was the first mammalian RNA kinase to be identified. However, determining its in vivo function has been elusive. Here we generated kinase-dead Clp1 (Clp1K/K ) mice that show a progressive loss of spinal motor neurons associated with axonal degeneration in the peripheral nerves and denervation of neuromuscular junctions, resulting in impaired motor function, muscle weakness, paralysis and fatal respiratory failure. Transgenic rescue experiments show that CLP1 functions in motor neurons. Mechanistically, loss of CLP1 activity results in accumulation of a novel set of small RNA fragments, derived from aberrant processing of tyrosine pre-transfer RNA. These tRNA fragments sensitize cells to oxidative-stress-induced p53 (also known as TRP53) activation and p53-dependent cell death. Genetic inactivation of p53 rescues Clp1K/K mice from the motor neuron loss, muscle denervation and respiratory failure. Our experiments uncover a mechanistic link between tRNA processing, formation of a new RNA species and progressive loss of lower motor neurons regulated by p53.

Date: 2013
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DOI: 10.1038/nature11923

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