Pre-symptomatic Parkinson’s disease blood test quantifying repetitive sequence motifs in transfer RNA fragments
Nimrod Madrer, Shani Vaknine, Tamara Zorbaz, Yonat Tzur, Estelle R. Bennett, Paz Drori, Nitzan Suissa, David Greenberg, Eitan Lerner, Eyal Soreq, Iddo Paldor, Hermona Soreq
Abstract
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. Madrer et al. identify a Parkinson’s disease–specific increase in transfer RNA (tRNA) fragments in human blood, cerebrospinal fluid and postmortem brain tissue, demonstrating the ability of blood-based tRNA fragment quantification to distinguish between pre-symptomatic patients and healthy controls.