Blood tests use RNA markers to detect Parkinson's disease before symptoms appear

Scientists have developed a fast, non-invasive blood test that can detect Parkinson's disease before the tremor begins. By measuring RNA fragments that reflect brain pathology, this test offers new hopes for early diagnosis and targeted interventions.

study: Quantification of repetitive sequence motifs in presymptomatic Parkinson's disease blood test metastatic RNA fragments. Image credit: Kateryna Kon/Shutterstock

A recent study published in the journal Natural agingresearchers evaluated whether blood tests measuring nuclear and mitochondrial mobile RNA (TRNA) fragments could accurately detect presymptomatic Parkinson's disease (PD).

background

What if we could detect PD before a single tremor begins? PD is the second most common neurodegenerative disorder worldwide, affecting more than 10 million people worldwide according to widely cited estimates, causing progressive movement and cognitive impairment. Current diagnostic methods are often reactive, identifying diseases after brain damage has already occurred. Invasive testing and inconsistent biomarkers further hinder early diagnosis. Transfer RNA fragments (TRFs), a small, non-coding RNA fragments produced by enzyme cleavage, have emerged as potential indicators of neurological damage. Their levels vary according to mitochondrial dysfunction and neural stress, both of which are characteristic of PD. However, further research is required to verify diagnostic capabilities.

About the research

The researchers conducted multicohort analysis using small RNA sequencing and quantitative polymerase chain reaction (QPCR) to explore the diagnostic potential of specific TRFs in PD. They analyzed healthy control cerebrospinal fluid, blood, and brain samples, including postmortem samples from the Dutch Brain Bank (NBB) and living donors of Parkinson's Progression Marker Initiative (PPMI). This study focused on two TRF families. Nuclearly constructed RGTTCRA-TRFS, derived from transfer RNA and marked by specific repetitive motifs ([A/G]GTTC[A/G]A) and mitochondrial TRFs (MT-TRFs) derived from the mitochondrial genome. The two ratios were calculated to standardize differences between individuals.

Using the PPMI dataset, they evaluated this ratio early stage, mutation– Carrie and precursor patients. Using dual QPCR, they also examined the findings of fresh blood samples (Shaare Zedek Medical Center Cohort) and postmortem brain tissue (NIH Neurobiobank). Additionally, we compared the predicted accuracy of the TRF ratio with traditional clinical scores such as the Unified Parkinson's Disease Rating Scale (UPDR) and the Hoehn and Yahr (H&Y) scale using Gradient-Boosted Machine Learning (GBM) model. Additional experiments included overexpression and knockout of Angiogenin (ANG), TRNA-cleaving enzymes, and ribosomal profiling to investigate the biological effects of RGTTCRA-TRF accumulation on protein synthesis.

Research Results

This study revealed distinct changes in PD-related transfer RNA fragments. In cerebrospinal fluid, patients had increased levels of RGTTCRA-TRF and decreased levels of MT-TRF compared to Alzheimer's disease controls and individuals. This unique TRF profile was consistent across both genders and did not overlap with symptoms of Alzheimer's disease. Similarly, brain tissue in the vast Nygra (the most affected area in PD) showed high RGTTCRA-TRF levels correlated with the presence of protein aggregates, a characteristic of the disease.

Blood analysis supported these findings. In postmortem samples, RGTTCRA-TRF was significantly increased and MT-TRF was reduced. Patients carrying early stage mutations showed a higher RGTTCRA/MT-TRF ratio than healthy carriers of the same mutation. This pattern was consistent across ethnic backgrounds, but slightly less clear in black participants, and parallels clinical score trends. Importantly, the GBM model using the TRF ratio achieved a diagnostic accuracy of 0.86 (area under the curve (AUC)), surpassing the traditional clinical score (AUC 0.73). The TRF signature also distinguished precursor patients and patients with early nonmotor symptoms from healthy controls.

Dual QPCR tests confirmed that this ratio could reliably separate patients from both fresh blood and postmortem brain samples. Furthermore, RGTTCRA-TRF levels were reduced after deep brain stimulation (DBS) treatment, consistent with the relief of clinical symptoms. Patients treated with DBS showed reduced RGTTCRA-TRF and reduced angiogenin (ANG), indicating that DBS may suppress TRF production or alter regulation.

Biological analysis provided insight into the potential pathogenic role of RGTTCRA-TRF. These fragments showed strong sequence complementarity to ribosomal RNA and fragments derived from leucag tRNA, essential for protein translation (Leucag3'-TRF). Interaction modelling suggested that RGTTCRA-TRF could combine both and create a “dual lock” mechanism that impairs translation initiation and elongation. Ribosomal profiling of depolarized neuroblastoma cells reduced the association between RGTTCRA-TRF and ribosomes, supporting its role in translational disruption. Förster resonance energy transfer (FRET) imaging confirmed the proximity between the RGTTCRA-TRF and the ribosome in living cells.

Conclusion

In summary, this study presents compelling evidence that RNA fragments (specifically, RGTTCRA-TRF and MT-TRF) may function as early non-invasive blood-based biomarkers of PD. These distinct patterns allow for accurate diagnosis even at the precursor stage, surpassing traditional clinical scoring. Dual QPCR tests are fast, cost-effective and sensitive, making them highly applicable in clinical settings. Furthermore, these TRFs may play a role in disease progression by interfering with protein synthesis. The findings need to be examined in larger, more diverse cohorts, particularly underestimated ethnic groups. Biomarkers Strategies provide a promising pathway for previous detection, better monitoring, and more effective therapeutic interventions in PD.