Early, efficient Parkinson's disease (PD) tests may facilitate pre-symptomatic diagnosis and disease-modifying therapies. Here we report elevated levels of PD-specific transfer RNA fragments carrying a conserved sequence motif (RGTTCRA-tRFs) in the substantia nigra, cerebrospinal fluid and blood of patients with PD. A whole blood qPCR test detecting elevated RGTTCRA-tRFs and reduced mitochondrial-originated tRFs (MT-tRFs) segregated pre-symptomatic patients with PD from controls (area under the receiver operating characteristic curve (ROC-AUC) of 0.75 versus 0.71 based on traditional clinical scoring). Strengthening PD relevance, patients carrying PD-related mutations presented higher blood RGTTCRA-tRFs/MT-tRFs ratios than mutation-carrying non-symptomatic controls, and RGTTCRA-tRF levels decreased in patients' blood after deep brain stimulation. Furthermore, RGTTCRA-tRFs complementarity to ribosomal RNA and the translation-supporting LeuCAG3-tRF might aggravate PD via translational inhibition, as reflected by disrupted ribosomal association of RGTTCRA-tRFs in depolarized neuroblastoma cells. Our findings show tRF involvement in PD and suggest a potential simple and safe blood test that may aid clinicians in pre-symptomatic PD diagnosis after validation in larger independent cohorts.
© 2025. The Author(s).