Novel cause for neurological disorders: tRNA modifications in the spotlight
The review article in Frontiers of Molecular Neuroscience turns the spotlight on the defects in tRNA modifications as the proximal cause of a range of neurological and neurodegenerative disorders in humans.
Figure 1: Schematic representation of the secondary structure of tRNA with post-transcriptionally modified residues in light orange and red. The residues marked in red are of relevance to human neurological disorders.
Our team has focused on deciphering the links between dopamine (DA, a key neurotransmitter) homeostasis and its relationship to stress and neurodegenerative disorders for the past several years. Our strategy changed recently to involve looking at defects in tRNA modifications as a proximate cause for disruption of DA homeostasis and hence of parkinsonian disorders. Most often, hypermodified nucleosides are found in the wobble position of tRNAs, which play a direct role in maintaining translational efficiency and fidelity, codon recognition etc. One such hypermodified base is Queuosine (Q), a complex modification of guanosine found at position 34 (wobble position) of the GUN anticodons of four tRNA species (tRNA)Tyr, Asn, Asp, His. Q plays an important role in tyrosine biosynthesis in mammals. It has also been shown that Q deficiency in eukaryotes compromises tyrosine production by increased tetrahydrobiopterin (BH4) oxidation to dihydrobiopterin (BH2). Both tyrosine and BH4 are essential in the biosynthesis pathway for DA. Our survey of other tRNA modifications led us to compile a body of knowledge in which we highlight the critical role played by defects in tRNA modifications as a molecular basis of some neurological disorders in humans (Figure 1). This sets the stage for the need of intensive characterization of tRNA modifications in humans at the enzymatic and mechanistic level. This will pave the way to understand how lack of such modifications are associated with neurological disorders with the ultimate goal of gaining insights into therapeutic interventions.
Bednářová A, Hanna M, Durham I, VanCleave T, England A, Chaudhuri A and Krishnan N (2017) Lost in Translation: Defects in Transfer RNA Modifications and Neurological Disorders. Front. Mol. Neurosci. 10:135.