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. WoolfMarkus Glatzel, Ruth Herbst, Javier Martinez, Josef M. Penninger

Research output: Contribution to journalArticle

105 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)474-480
Number of pages7
JournalNature
Volume495
Issue number7442
DOIs
Publication statusPublished - 2013 Mar 28

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'CLP1 links tRNA metabolism to progressive motor-neuron loss'. Together they form a unique fingerprint.

  • Cite this

    Hanada, T., Weitzer, S., Mair, B., Bernreuther, C., Wainger, B. J., Ichida, J., Hanada, R., Orthofer, M., Cronin, S. J., Komnenovic, V., Minis, A., Sato, F., Mimata, H., Yoshimura, A., Tamir, I., Rainer, J., Kofler, R., Yaron, A., Eggan, K. C., ... Penninger, J. M. (2013). CLP1 links tRNA metabolism to progressive motor-neuron loss. Nature, 495(7442), 474-480. https://doi.org/10.1038/nature11923