title: CLP1 links tRNA metabolism to progressive motor-neuron loss.
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.
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.
authors.forename: Toshikatsu
authors.initials: T
authors.lastname: Hanada
authors.forename: Stefan
authors.initials: S
authors.lastname: Weitzer
authors.forename: Barbara
authors.initials: B
authors.lastname: Mair
authors.forename: Christian
authors.initials: C
authors.lastname: Bernreuther
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Wainger
authors.forename: Justin
authors.initials: J
authors.lastname: Ichida
authors.forename: Reiko
authors.initials: R
authors.lastname: Hanada
authors.forename: Michael
authors.initials: M
authors.lastname: Orthofer
authors.forename: Shane J
authors.initials: SJ
authors.lastname: Cronin
authors.forename: Vukoslav
authors.initials: V
authors.lastname: Komnenovic
authors.forename: Adi
authors.initials: A
authors.lastname: Minis
authors.forename: Fuminori
authors.initials: F
authors.lastname: Sato
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Mimata
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Ido
authors.initials: I
authors.lastname: Tamir
authors.forename: Johannes
authors.initials: J
authors.lastname: Rainer
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kofler
authors.forename: Avraham
authors.initials: A
authors.lastname: Yaron
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Eggan
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.forename: Ruth
authors.initials: R
authors.lastname: Herbst
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D000690:Amyotrophic Lateral Sclerosis; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D003964:Diaphragm / Q000294:innervation; D020964:Embryo Loss; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005091:Exons / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology*; D009134:Muscular Atrophy, Spinal; D009468:Neuromuscular Diseases / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D012323:RNA Processing, Post-Transcriptional; D012365:RNA, Transfer, Tyr / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D012119:Respiration; D013127:Spinal Nerves / Q000166:cytology; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: C118642:Hexim1 protein, mouse; D012365:RNA, Transfer, Tyr; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D014443:Tyrosine