Transfer RNAs (tRNAs) represent the most abundant class of
RNA molecules in the cell and are key players during
protein synthesis and cellular homeostasis. Aberrations in the extensive
tRNA biogenesis pathways lead to severe
neurological disorders in humans. Mutations in the
tRNA splicing endonuclease (TSEN) and its associated
RNA kinase cleavage factor polyribonucleotide
kinase subunit 1 (CLP1) cause
pontocerebellar hypoplasia (PCH), a heterogeneous group of
neurodegenerative disorders, that manifest as underdevelopment of specific brain regions typically accompanied by
microcephaly, profound motor impairments, and child mortality. Recently, we demonstrated that mutations leading to specific PCH subtypes destabilize TSEN in vitro and cause imbalances of immature to mature
tRNA ratios in patient-derived cells. However, how
tRNA processing defects translate to disease on a systems level has not been understood. Recent findings suggested that other cellular processes may be affected by mutations in TSEN/CLP1 and obscure the molecular mechanisms of PCH emergence. Here, we review PCH disease models linked to the TSEN/CLP1 machinery and discuss future directions to study neuropathogenesis.