Alanine tRNA fragments interacting with MEG3 long splice variant show tissue-, cellular compartment- and disease severity-dependent changes in Parkinson’s disease

Long non-coding RNAs (lncRNAs) and tRNA fragments (tRFs) have emerged as important regulators in Parkinson’s disease (PD), but much remains unknown regarding their interactions. We report here that the long splice variant of MEG3 lncRNA interacts with alanine tRNA 3’-end fragments (3’-tRFs-Ala), and that both showed dysregulated levels in the substantia nigra of PD patients. Additionally, carriers of PD-risk mutations ( LRRK2 +, GBA +, SNCA +) had decreased levels of 3’-tRFs-Ala in their blood, and in GBA + PD patients, reduced levels correlated with the severity of autonomic and sensory non-motor impairments. Paraquat-induced oxidative stress in neuroblastoma cells decreased 3’-tRFs-Ala levels in the nucleus but increased them in the cytoplasm, highlighting acute changes in subcellular localization. Simultaneously, 3’-tRFs-Ala bind nuclear spliceosome and cytoplasmic aminoacyl-tRNA synthetase proteins, suggesting an additional level of post-transcriptional regulation in neuronal and peripheral immune cells. Overall, the interacting MEG3 long splice variant and 3’-tRFs-Ala emerged as non-coding RNAs with dynamic and spatiotemporal roles in PD pathology.