Neurological Diseases Caused by Loss of Transfer RNA Modifications: Commonalities in Their Molecular Pathogenesis

Human transfer RNA (tRNA) contains 46 post-transcriptional modifications at specific tRNA positions, which are incorporated by specific modifying enzymes. These tRNA modifications support the structural and biochemical stability of tRNAs and codon-anticodon interactions. Pathogenic genetic variants and disease-associated expressional aberrations have been identified in more than 50 human tRNA modification enzymes and their partner proteins. These are the causes of various diseases and disorders collectively termed 'tRNA modopathies.' Nervous tissue is the most affected tissue in the body upon loss of tRNA modifications, and 37 tRNA modification writers have pathogenic variants that cause neurological diseases. Here, we describe the molecular functions of human tRNA modifications and provide a thorough compilation of >80 human tRNA modification writers and neurological tRNA modopathies. Although largely unexplored, there is growing evidence for the pathogenic mechanisms of neurological tRNA modopathies. Loss of tRNA modifications can cause tRNA destabilization, altered decoding, or production of toxic tRNA fragments, which lead to the severely dysregulated proteostasis that causes neurodegeneration, or the mild translational defects that cause memory impairment. We present herein an overview of these mechanisms and discuss the development of therapeutic strategies and future avenues of research to determine the exact role of tRNA modifications in the nervous system.