CLP1 links tRNA metabolism to progressive motor-neuron loss

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. Inactivating the CLP1 RNA kinase in mice leads to a progressive loss of motor neurons, through a mechanism related to the accumulation of a novel set of small RNA fragments derived from aberrant processing of tyrosine pre-transfer RNA. The mammalian RNA kinase CLP1 was first identified nearly five years ago, when its in vivo function was unclear. Since then RNA metabolism has come to the forefront of biology, and now using knockout mice, CLP1 has been found to act in motor neurons. Mice with an inactive CLP1 kinase show progressive loss of spinal motor neurons, peripheral neurodegeneration and impaired motor function culminating in respiratory failure. Loss of CLP1 activity results in accumulation 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 mutant mice from the neuromuscular signs of CLP1 inactivation. These data reveal a previously unknown link between tRNA processing, a new RNA species and a p53-regulated progressive loss of lower motor neurons. These findings might help to explain the molecular basis of diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy.