Transfer RNA Fragments in Cerebrospinal Fluid and Blood: Implications for Neurodegenerative Diseases

Significance

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.

About the author

Hermona Soreq studied at The Hebrew University, Tel Aviv University, The Weizmann Institute and the Rockeffeler University. She holds a Hebrew University Slesinger Chair in Molecular Neuroscience and is a founding member of the Edmond and Lily Safra Center for Brain Science. Soreq explores long and short non-coding RNA regulators of acetylcholine in health and disease, especially microRNAs and transfer RNA fragments (CholinomiRs, CholinotRFs). She explores the complex impact of these non-coding RNA controllers on brain-to-body functioning, which is largely unresolved, and in particular, her work addresses microRNAs (miRs) and transfer RNA fragments (tRFs) which rapidly acquire wide recognition as global controllers of regulatory processes at large. Soreq’s research focuses on acetylcholine(ACh)-related pathways and combines advanced computational neuroscience with RNA-sequencing technologies, transgenic engineering and microscopy analysis She investigates controlller RNA functions in the healthy and diseased brain and body, and discovered primate-specific “CholinomiR” silencers of multiple genes that compete with each other on suppressing their targets (Barbash et al., Evolution and Molecular Biology 2014). Further, her team identified cholinergic brain-to-body regulation of anxiety and inflammation (Soreq, Trends Neurosci., 2015). In israeli human volunteers, Soreq found cholinergic-associated pulse increases under fear of terror (Shenhar-Tsarfaty et al., PNAS 2015); and identified massive CholinomiRs decline in Alzheimer’s brains (Barbash et al., Neurobiol. Disease 2017), which accompanies changes in long non-coding RNAs and points at Statins and circular RNA interventions with Parkinson’s disease progression (Simchovitz et al., Aging Cell 2020, Hanan et al., EMBO Mol Med 2020). In both engineered mice and human patients, Soreq studies CholinomiR and CholinotRF responders to inflammation (Shaked et al., Immunity 2009), ischemic stroke (Winek et al., PNAS 2020), epilepsy (Bekenstein et al., PNAS 2017) and liver fattenning (Hanin et al., Gut 2018), as well as altered traumatic reactions (Lin et al., Translational Psychiatry 2016). She has further reported CholinomiR differences between men and women living with schizophrenia and bipolar disorder (Lobentanzer et al., Cell Rep. 2019; Simchovitz-Gesher & Soreq, TIPS 2020), and modified structure of cholinergic interneurons under mild social stress (Yayon et al., EMBO J 2023). Further, Soreq’s work demonstrated depletion of mitochondrial-originated CholinotRFs in women living with alzheimer’s disease as associated with their expedite cognitive decline (Shulman et al., Alzheimer’s&Dementia 20123). Altogether, Soreq’s work leads to molecular neuroscience-driven prevention and/or intervention with diseases involving impaired ACh signaling.

Reference

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.

Go To J Neurochem.