Cerebrospinal fluid (CSF) biomarkers play a pivotal role in the diagnosis, prognosis, and management of numerous neurological and neurodegenerative disorders. These biomarkers are substances in the CSF that offer insights into the health and functioning of the central nervous system (CNS). For instance, CSF biomarkers facilitate the early diagnosis of neurological diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and various dementias. Early detection enables timely intervention and treatment, potentially slowing disease progression and enhancing patient outcomes. These biomarkers can also differentiate between neurological disorders with overlapping clinical symptoms. For example, they can distinguish between Alzheimer’s disease and other dementias, such as frontotemporal or vascular dementia. This differentiation is crucial for tailored treatment and care. Additionally, CSF biomarkers can monitor the progression of neurodegenerative diseases. Variations in biomarker levels furnish clinicians with vital insights into disease severity and the efficacy of therapeutic interventions. By examining CSF composition and tracking protein changes over time, researchers can delve deeper into the mechanisms underlying brain diseases, paving the way for groundbreaking discoveries and potential treatments. It’s essential to note that CSF composition varies from peripheral blood, encompassing unique elements from both blood and the CNS. For example, protein levels in CSF are markedly lower than in blood; elevated protein levels in CSF often indicate pathological changes.
Transfer RNAs (tRNAs) are the most abundant class of ncRNA molecules in the human transcriptome, accounting for 4–10% of all cellular RNAs. The primary role of tRNAs is to decode genetic information, translating it into amino acid sequences. Recent advancements in sequencing technology have identified a novel class of small non-coding RNAs (sncRNAs) derived from tRNAs, known as tRNA-derived fragments (tRFs). These fragments, specific cleavage products of both pre-tRNAs and mature tRNAs, are evolutionarily conserved. tRFs can be classified into various subtypes based on cleavage sites and lengths: 5′-tRFs, 3′-tRFs, i-tRFs, 5′-half tRFs, and 3′-half tRFs. Emerging evidence pinpoints tRFs as key players in gene regulation, and they’ve been linked to various ailments, including cancer and neurodegenerative disorders.
A recent study in the Journal of Neurochemistry, led by Professor Hermona Soreq from the Hebrew University of Jerusalem, compared tRF profiles in CSF and blood, focusing on the influences of sex, age, and Parkinson’s disease (PD) on these profiles. They identified pronounced differences between tRFs in CSF and blood, highlighting the significance of examining tRFs within the CSF context for neurological conditions. For instance, CSF tRFs displayed more diversity in length and cleavage subtypes than blood tRFs. Although both CSF and blood contained i-tRFs, blood was predominantly composed of 3′-tRFs, whereas 3′-half tRFs were scarce in the blood. These distinctions indicate that CSF may harbor a more varied array of tRFs. The team also uncovered sex-related variations in tRF profiles, with more pronounced disparities in CSF than in blood, underscoring the necessity of factoring in sex-specific effects in neurological research. Age-related alterations in tRF levels were also observed, especially in CSF, revealing potential links to age-associated neurodegenerative diseases.
Professor Soreq’s team further examined the differences in tRF profiles between PD patients and healthy controls. They observed distinct tRF profiles in both groups, with the disparities more evident in blood than in CSF. These variances were linked to unique tRF subsets, suggesting specialized roles for tRFs in PD. An intriguing facet of their research was the correlation between the cellular origin of tRFs and their potential to target cholinergic genes, crucial for modulating cognition and behavior. Mitochondrial-originated tRFs were notably enriched in potential Cholino-tRFs, indicating that mitochondrial dysfunction, a characteristic of many neurodegenerative diseases, might influence cholinergic balance through these tRFs.
In conclusion, Professor Soreq and her team highlighted the potential of tRFs as biomarkers in both CSF and blood. Their findings underscore the importance of examining tRFs within the CNS milieu and shed light on how sex, age, and diseases like PD might alter tRF profiles. The recognition of mitochondrial-originated Cholino-tRFs hints at a connection between mitochondrial dysfunction and cholinergic imbalance. This revelation creates opportunities for more in-depth research and potential therapeutic solutions. Future investigations on tRFs may uncover innovative diagnostic and treatment strategies for neurodegenerative disorders, edging us closer to enhanced treatments and patient outcomes.
Paldor I, Madrer N, Vaknine Treidel S, Shulman D, Greenberg DS, Soreq H. Cerebrospinal fluid and blood profiles of transfer RNA fragments show age, sex, and Parkinson’s disease-related changes. J Neurochem. 2023 ;164(5):671-683. doi: 10.1111/jnc.15723.