April 2025: AD/PD International Conference, Vienna, Austria

PRE-SYMPTOMATIC BLOOD CELLS DIAGNOSIS OF PARKINSON’S DISEASE-ESCALATED MOTIF-SHARING TRANSFER RNA FRAGMENTS DECLINED UNDER DEEP BRAIN STIMULATION,

Dr. Hermona Soreq, Hebrew University

Abstract: Rapid, simple and reliable Parkinson’s disease (PD) blood tests may enable pre-symptomatic diagnosis and facilitate disease-changing treatments. Here, we report elevated levels in PD patients’ substantia nigra, cerebrospinal fluid and blood of PD-specific nuclear genome-originated tRNA fragments (PD-tRFs) carrying a conserved sequence motif. A dual whole blood RNA-based test using qPCR primers for elevated PD-tRFs and reduced mitochondrial-originated tRFs (MT-tRFs) successfully distinguished pre-symptomatic PD patients from controls, outperforming traditional clinical scoring (ROC-AUC of 0.86 vs. 0.73). Strengthening relevance to disease characteristics, symptomatic PD patients carrying PD-related mutations presented higher blood PD-tRFs/MT-tRFs ratios than mutations-carrying non-symptomatic individuals. Furthermore, PD-tRFs complementarity to ribosomal RNA and the translation-supporting LeuCAG3 tRF might escalate disease symptoms via ‘dual-lock’ translational inhibition. Correspondingly, PD-tRFs levels declined in patients’ blood following deep brain stimulation and their ribosomal association was disrupted in depolarized neuroblastoma cells. Our findings facilitate a sensitive, simple and safe blood test for pre-symptomatic PD.