Journal article
CLP1 links tRNA metabolism to progressive motor-neuron loss
Nature, Vol.495(7442), pp.474-480
Mar/2013
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 (Clp1(K/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 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.
Details
- Title
- CLP1 links tRNA metabolism to progressive motor-neuron loss
- Creators
- Toshikatsu Hanada (null)Stefan Weitzer (null)Barbara Mair (null)Christian Bernreuther (null)Brian J. Wainger (null)Justin Ichida (null)Reiko Hanada (null)Michael Orthofer (null)Shane J. Cronin (null)Vukoslav Komnenovic (null)Adi Minis (null) - 972WIS_INST___112Fuminori Sato (null)Hiromitsu Mimata (null)Akihiko Yoshimura (null)Ido Tamir (null)Johannes Rainer (null)Reinhard Kofler (null)Avraham Yaron (null) - 972WIS_INST___112Kevin C. Eggan (null)
- Resource Type
- Journal article
- Publication Details
- Nature, Vol.495(7442), pp.474-480; Mar/2013
- Number of pages
- 7
- Language
- English
- DOI
- https://doi.org/10.1038/nature11923
- Grant note
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA); Austrian Ministry of Sciences; Austrian Academy of Sciences; AustroMouse network of Genome Research in Austria (GEN-AU); Apoptosis systems biology applied to cancer and AIDS (ApoSys); European Research Council Advanced Grant from the European Union; IMBA; GEN-AU (AustroMouse); Japan Society for the Promotion of Science; Astellas Foundation; National Institutes of Health (NIH) [K99NS077435-01A1]; German Research Foundation (DFG) [FG885, GRK 1459]; Landesexzellenzinitiative Hamburg (Neurodapt); Austrian Science Fund [P19223, P21667]; NIH [NS038253]We thank A. Meixner, M. Foong, T. Nakashima, H. C. Theussl, J. R. Wojciechowski, A. Bichl, the mouse pathology unit of the Universitatsklinikum Hamburg-Eppendorf, and G. P. Resch for discussions and technical support. We also thank T. Buerckstuemmer for providing the pRV-NTAP vector. J. M. P. is supported by grants from the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), the Austrian Ministry of Sciences, the Austrian Academy of Sciences, AustroMouse network of Genome Research in Austria (GEN-AU), Apoptosis systems biology applied to cancer and AIDS (ApoSys) and a European Research Council Advanced Grant from the European Union. J. M., S. W. and B. M. are supported by IMBA and GEN-AU (AustroMouse). T. H. is supported by the Japan Society for the Promotion of Science and the Astellas Foundation. J. K. I. was supported by National Institutes of Health (NIH) grant K99NS077435-01A1. M. G. is supported by grants from the German Research Foundation (DFG) (FG885 and GRK 1459), the Landesexzellenzinitiative Hamburg (Neurodapt). R. H. was supported by the Austrian Science Fund (P19223, P21667). C. J. W. is supported by the NIH (NS038253)._ALMAME_DELIMITER_
- Record Identifier
- 993267031603596
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