Transfer RNAs and Neurodegenerative Disorders

Among all biomolecules within the cell, tRNAs got the least respect. Their supposed importance ended right after the ‘adaptors’ related to entries in the genetic code table were identified (mid-60s). Since then, the attention shifted to more complex RNAs like the rRNAs.

Interestingly, tRNAs are making major comeback and that too in the most unexpected places. Several groups linked them with neurodegenerative disorders. Is that due to too much money looking for causes of complex diseases, or are tRNAs indeed more remarkable than previously thought?

Here is a paper from 2013 that made major splash by linking tRNAs with diseases, but there are a few additional ones.

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.