Blood test detects Parkinson’s years before symptoms appear using RNA markers

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Blood test detects Parkinson’s years before symptoms appear using RNA markers

Scientists have developed a fast, non-invasive blood test that can detect Parkinson’s disease before tremors begin. By measuring RNA fragments that reflect brain pathology, the test offers new hope for early diagnosis and targeted intervention.

In a recent study published in the journal Nature Aging, researchers evaluated whether a blood test measuring nuclear and mitochondrial transfer RNA (tRNA) fragments could accurately detect pre-symptomatic Parkinson’s disease (PD).

Background

What if we could detect PD before a single tremor begins? PD is the second most common neurodegenerative disorder globally, affecting over 10 million people worldwide according to widely cited estimates and causing progressive movement and cognitive impairments. Current diagnostic methods are often reactive, identifying the disease after significant brain damage has already occurred. Invasive tests and inconsistent biomarkers further hinder early diagnosis. Transfer RNA fragments (tRFs), small non-coding RNA pieces generated by enzymatic cleavage, are emerging as potential indicators of neurological disorders. Their levels shift in response to mitochondrial dysfunction and neuronal stress, both hallmarks of PD. However, further research is needed to validate their diagnostic power.

About the Study

Patient-specific “fingerprints”: Blood tRF levels remained stable over time in individuals, creating unique molecular profiles that could enable personalized tracking of disease progression.

Researchers conducted a multi-cohort analysis using small RNA sequencing and quantitative polymerase chain reaction (qPCR) to explore the diagnostic potential of specific tRFs in PD. They analyzed cerebrospinal fluid, blood, and brain samples from patients with PD, Alzheimer’s disease, and healthy controls, including postmortem samples from the Netherlands Brain Bank (NBB) and living donors from the Parkinson’s Progression Markers Initiative (PPMI). The study focused on two tRF families: nuclear-originated RGTTCRA-tRFs, derived from transfer RNA and marked by a specific repetitive motif ([A/G]GTTC[A/G]A), and mitochondrial tRFs (MT-tRFs), originating from mitochondrial genomes. A ratio between the two was calculated to standardize differences across individuals.

Using the PPMI dataset, they evaluated this ratio in early-stage, mutation-carrying, and prodromal patients. Using dual qPCR, they also validated the findings in fresh blood samples (Shaare Zedek Medical Center cohort) and postmortem brain tissues (NIH NeuroBioBank). Furthermore, they used a gradient-boosted machine learning (GBM) model to compare the predictive accuracy of the tRF ratio to traditional clinical scores like the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Hoehn and Yahr (H&Y) scale. Additional experiments included overexpression and knockout of angiogenin (ANG), a tRNA-cleaving enzyme, and ribosomal profiling to examine the biological effects of RGTTCRA-tRF accumulation on protein synthesis.

Study Results

The study revealed distinct changes in transfer RNA fragments associated with PD. In cerebrospinal fluid, patients exhibited elevated levels of RGTTCRA-tRFs and decreased levels of MT-tRFs compared to controls and individuals with Alzheimer’s disease. This unique tRF profile was consistent in both sexes and showed no overlap with Alzheimer’s disease signatures. Similarly, brain tissue from the substantia nigra (the region most affected in PD) showed high RGTTCRA-tRF levels correlating with the presence of Lewy bodies, protein aggregates that are a hallmark of the disease.

Mitochondrial tRNA collapse: Postmortem brain tissue showed mitochondrial tRNA levels dropped as Parkinson’s advanced, mirroring CSF trends and highlighting organelle failure as a disease driver.

Blood analysis supported these findings. In postmortem samples, RGTTCRA-tRFs were significantly elevated while MT-tRFs were reduced. Early-stage, mutation-carrying patients displayed a higher RGTTCRA/MT-tRF ratio than healthy carriers of the same mutation. This pattern was consistent across ethnic backgrounds, though slightly less distinct in Black participants, paralleling trends in their clinical scores. Importantly, the GBM model using the tRF ratio achieved a diagnostic accuracy (area under the curve (AUC)) of 0.86, outperforming traditional clinical scores (AUC 0.73). The tRF signature also distinguished prodromal patients, those with early, non-motor symptoms, from healthy controls.

Dual qPCR tests confirmed that this ratio could reliably segregate patients from controls in both fresh blood and postmortem brain samples. Further, RGTTCRA-tRF levels decreased after deep brain stimulation (DBS) treatment, aligning with clinical symptom relief. Patients treated with DBS showed reduced RGTTCRA-tRFs and decreased expression of angiogenin (ANG), indicating that DBS may suppress tRF production or alter their regulation.

Biological analyses provided insight into the potential pathogenic role of RGTTCRA-tRFs. These fragments showed strong sequence complementarity to ribosomal RNA and a leucine tRNA-derived fragment essential for protein translation (LeuCAG3′-tRF). Interaction modeling suggested that RGTTCRA-tRFs could bind both, creating a “dual-lock” mechanism that impairs translation initiation and elongation. Ribosomal profiling of depolarized neuroblastoma cells revealed reduced association of RGTTCRA-tRFs with ribosomes, supporting their role in translation disruption. Förster resonance energy transfer (FRET) imaging confirmed close proximity between RGTTCRA-tRFs and ribosomes in live cells.

Conclusions

To summarize, this study presents compelling evidence that transfer RNA fragments (specifically, RGTTCRA-tRFs and MT-tRFs) can serve as early, non-invasive blood-based biomarkers for PD. Their distinct pattern enables accurate diagnosis even in prodromal stages, outperforming traditional clinical scoring. The dual qPCR test is fast, cost-effective, and sensitive, making it highly applicable in clinical settings. Moreover, these tRFs may play a role in disease progression by interfering with protein synthesis. While findings require validation in larger and more diverse cohorts, particularly in underrepresented ethnic groups, this biomarker strategy offers a promising path toward earlier detection, better monitoring, and more effective therapeutic intervention in PD.

Journal reference:

• Madrer, N., Vaknine-Treidel, S., Zorbaz, T. et al. Pre-symptomatic Parkinson’s disease blood test quantifying repetitive sequence motifs in transfer RNA fragments. Nat Aging (2025), DOI: 10.1038/s43587-025-00851-z, https://www.nature.com/articles/s43587-025-00851-z