Pre-symptomatic qPCR blood test based on Parkinson's disease-specific angiogenin-derived transfer RNA fragments

Rapid, simple and reliable blood tests for Parkinson's disease (PD) may enable pre-symptomatic diagnosis and facilitate disease-changing treatments. Here, we report escalated elevated levels of angiogenin-cleaved a disease specific group of nuclear genome-originated tRNA fragments (hereafter, PD-tRFs) carrying a unique seven-nucleotide motif in substantia nigra, cerebrospinal fluid and blood of PD patients. A blood test using RNA isolated from whole blood and dual multiplexl qPCR primers for PD-tRFs and 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). Indicating relevance to disease symptoms, PD patients carrying GBA, SNCA or LRRK2 mutations presented elevated blood PD/MT-tRF ratios compared to mutations-carrying non-symptomatic individuals which indicates relevance to disease symptoms. Furthermore, PD-tRFs' potential for ribosomal association predicted translational inhibition. Intriguingly, PD-tRFs levels declined both in patients' blood following deep brain stimulation andas well as in in depolarized neuroblastoma cells where PD-tRFs presented transientlydepolirization impaired impacted ribosomal associations. Our findings facilitate a sensitive and accurate blood test for early PD. Overall design: 37 blood samples of Parkinson's disease (PD) and controls, as well as 8 substantia nigra samples of PD patients were used to exteact short RNA. PD patients had various disease durations and Lewy bodies scores.