The RNA kinase CLP1 links tRNA metabolism to progressive motor neuron loss

• Published in: Nature (London) 2013-03, Vol.495 (7442), p.474-480
• Main Authors: Hanada, Toshikatsu, Weitzer, Stefan, Mair, Barbara, Bernreuther, Christian, Wainger, Brian J., Ichida, Justin, Hanada, Reiko, Orthofer, Michael, Cronin, Shane J, Komnenovic, Vukislav, Minis, Adi, Sato, Fuminori, Mimata, Hiromitsu, Yoshimura, Akihiko, Tamir, Ido, Rainer, Johannes, Kofler, Reinhard, Yaron, Avraham, Eggan, Kevin C., Woolf, Clifford J., Glatzel, Markus, Herbst, Ruth, Martinez, Javier, Penninger, Josef M.
• Format: Article
• Language: English
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11923

CLP1 is the first discovered mammalian RNA kinase. However, its in vivo function has been entirely elusive. We have generated kinase-dead Clp1 ( Clp1 K/K ) mice which exhibit a progressive loss of spinal motor neurons associated with axonal degeneration in peripheral nerves, denervation of neuromuscular junctions, and results 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 an entirely novel set of small RNA fragments, derived from aberrant processing of tyrosine pre-tRNA. These tRNA fragments sensitize cells to oxidative stress-induced p53 activation and p53-dependent cell death. Genetic inactivation of p53 rescues Clp1 K/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.