Given sufficient sensitivity and the right target, many age-related conditions could be detected in their earliest, pre-symptomatic stages. Early detection offers a greater opportunity to change course to slow progression, even with the techniques of today. Here, researchers note a specific transfer RNA fragment that appears in the context of Parkinson’s disease. Transfer RNAs are necessary for the process of translation, where proteins are produced from the template of a messenger RNA by a ribosome. The transfer RNA shows the ribosome how to translate messenger RNA sequences to specific protein amino acid sequences. Thus widespread changes in cell status could in principle be reflected in some way in circulating remnants of transfer RNA, given sufficient sensitivity for a test.
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. PD diagnosis often follows considerable neuronal damage manifested as severe motor impairments, such as bradykinesia, rigidity, and tremors. However, earlier symptoms, including smell loss and rapid eye movement sleep disorders, may appear years beforehand. Molecular changes characteristic of this early disease phase may constitute a basis for a pre-symptomatic diagnostic test.
Recent PD diagnostic tests have focused on elevated cerebrospinal fluid (CSF) levels of the α-synuclein (α-Syn) protein or reduced blood mitochondrial DNA as biomarkers. However, CSF sampling is invasive; purification and detection of α-Syn are cumbersome and insufficiently sensitive; and measurements of specific proteins show high inter-individual variability. Ideally, an easy, safe and affordable diagnosis should be based on multiple highly sensitive and specific blood biomarkers.
From our study, transfer RNA fragments (tRFs) carrying a conserved sequence motif (RGTTCRA-tRFs) emerged as potentially suitable biomarkers that may constitute patient-specific ‘fingerprints’ and carry short conserved sequence motifs that enable single measurement of multiple tRFs. Intriguingly, we found that RGTTCRA-tRFs accumulate in the brain, CSF and blood of male and female patients with PD at diverse disease stages but not in matched controls or in patients with Alzheimer’s disease. Moreover, motif-carrying RGTTCRA-tRFs consistently showed linkage to PD symptoms and disease stages, and their levels were elevated in correlation with Lewy body scores in patients’ substantia nigra.
Additionally, part of the identified RGTTCRA-tRFs stem from tRNAs that carry phenylalanine or cysteine amino acids, known to be the rate-limiting factors in the dopamine synthesis and in glutathione reductase antioxidant mechanism, respectively. Thus, shortage of these intact tRNAs (as they are enzymatically cut into the observed tRFs) may correspond to impaired dopamine synthesis or to processes that limit cellular antioxidation. Compatible with the known mitochondrial damage in PD (which leads to general reduction in mitochondrial transcript levels), we further found reduced levels of mitochondrial tRFs in the CSF and substantia nigra of idiopathic PD patients and in the blood of early PD patients carrying disease-related mutations.
Link: https://doi.org/10.1038/s43587-025-00851-z
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