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Aims: Maternally inherited diabetes and deafness (MIDD) is a rare form of adult‐onset diabetes that can be difficult to diagnose due to its variable clinical phenotype. Transfer RNA‐derived small fragments are a novel, emerging class of small non‐coding RNAs (sncRNAs) that have significant potential as serum biomarkers due to their stress‐induced generation, abundance, stability and ease of detection. Methods: We investigated the levels of tiRNA 5'ValCAC (alone and in combination with miR‐23b‐3p) identified from small RNA sequencing studies in serum samples from healthy controls, type 1 diabetes, type 2 diabetes and MIDD subjects. Results: Serum levels of 5'ValCAC were reduced in MIDD and type 2 diabetes subjects compared to controls. Type 2 diabetes subjects had higher serum levels of miR‐23b‐3p compared to all other subjects. Receiver Operating Characteristic analysis showed the potential of 5'ValCAC and miR‐23b‐3p as MIDD biomarkers, with the combination showing excellent separation from type 2 diabetes subjects. Conclusions: This is the first report showing altered serum levels of tiRNAs in diabetes subjects. The combined use of 5'ValCAC and miR‐23b‐3p as serum biomarkers could potentially differentiate between MIDD subjects and type 2 diabetes subjects. [ABSTRACT FROM AUTHOR]

An ALS-linked mutation in TDP-43 disrupts normal protein interactions in the motor neuron response to oxidative stress. Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction. An ALS-linked mutation in TDP-43 disrupts normal protein interactions in the motor neuron response to oxidative stress. Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction. [Extracted from the article]

Modification of tRNA is an integral part of the epitranscriptome with a particularly pronounced potential to generate diversity in RNA expression. Eukaryotic tRNA contains modifications in up to 20% of their nucleotides, but not all sites are always fully modified. Combinations and permutations of partially modified sites in tRNAs can generate a plethora of tRNA isoforms, termed modivariants. Here, we investigate the stoichiometry of incompletely modified sites in tRNAs from human cell lines for their information content. Using a panel of RNA modification mapping methods, we assess the stoichiometry of sites that contain the modifications 5-methylcytidine (m 5 C), 2'-O-ribose methylation (Nm), 3-methylcytidine (m 3 C), 7-methylguanosine (m 7 G), and Dihydrouridine (D). We discovered that up to 75% of sites can be incompletely modified and that the differential modification status of a cellular tRNA population holds information that allows to discriminate e.g. different cell lines. As a further aspect, we investigated potential causal connectivity between tRNA modification and its processing into tRNA fragments (tiRNAs and tRFs). Upon exposure of cultured living cells to cell-penetrating angiogenin, the modification patterns of the corresponding RNA populations was changed. Importantly, we also found that tsRNAs were significantly less modified than their parent tRNAs at numerous sites, suggesting that tsRNAs might derive chiefly from hypomodified tRNAs., Competing Interests: Mark Helm is a consultant for Moderna Inc., (© 2022 The Author(s).)

Progressive neuronal injury following ischaemic stroke is associated with glutamate-induced depolarization, energetic stress and activation of AMP-activated protein kinase (AMPK). We here identify a molecular signature associated with neuronal AMPK activation, as a critical regulator of cellular response to energetic stress following ischaemia. We report a robust induction of microRNA miR-210-3p both in vitro in primary cortical neurons in response to acute AMPK activation and following ischaemic stroke in vivo. Bioinformatics and reverse phase protein array analysis of neuronal protein expression changes in vivo following administration of a miR-210-3p mimic revealed altered expression of phosphatase and tensin homolog (PTEN), 3-phosphoinositide-dependent protein kinase 1 (PDK1), ribosomal protein S6 kinase (p70S6K) and ribosomal protein S6 (RPS6) signalling in response to increasing miR-210-3p. In vivo, we observed a corresponding reduction in p70S6K activity following ischaemic stroke. Utilizing models of glutamate receptor over-activation in primary neurons, we demonstrated that induction of miR-210-3p was accompanied by sustained suppression of p70S6K activity and that this effect was reversed by miR-210-3p inhibition. Collectively, these results provide new molecular insight into the regulation of cell signalling during ischaemic injury, and suggest a novel mechanism whereby AMPK regulates miR-210-3p to control p70S6K activity in ischaemic stroke and excitotoxic injury., (© 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Background and Purpose: Stroke is the second leading cause of death and disability worldwide and its diagnosis, and assessment of prognosis, remains challenging. There is a need for improved diagnostic and prognostic biomarkers. MicroRNAs (miRNAs) play important roles in the post-transcriptional regulation of gene expression and their secretion and remarkable stability in biofluids highlights their potential as sensitive biomarkers in the diagnosis and prognosis of acute stroke., Methods: We carried out a systematic review to assess current evidence supporting the potential of miRNAs to act as unique diagnostic and prognostic biomarkers in blood samples collected from patients suffering acute stroke within 24 hours of symptoms onset., Results: We identified 22 studies eligible for inclusion with 33 dysregulated miRNAs having diagnostic potential in the acute phase of the disease. We identified miR-16, miR-126, and miR-335 as having the highest sensitivity as diagnostic and prognostic biomarkers in acute ischaemic stroke and present original bioinformatic and pathway enrichment analysis of putative miRNA-target interactions., Conclusions: miRNAs represent unique biomarkers which have a promising future in stroke diagnosis and prognosis. However, there is a need for more standardized and consistent methodology for the accurate interpretation and translation of miRNAs as novel specific and sensitive biomarkers into clinical practice.

In this review, we summarise the evidence for a role of the ribonuclease angiogenin in the pathophysiology of neurodegenerative disorders, with a specific focus on Parkinson's disease (PD). Angiogenin is a stress-induced, secreted ribonuclease with both nuclear and cytosolic activities. Loss-of-function mutations in the angiogenin gene (ANG) have been initially discovered in familial cases of amyotrophic lateral sclerosis (ALS), however, variants in ANG have subsequently been identified in PD and Alzheimer's disease. Delivery of angiogenin protein reduces neurodegeneration and delays disease progression in in vitro and in vivo models of ALS and in vitro models of PD. In the nucleus, angiogenin promotes ribosomal RNA transcription. Under stress conditions, angiogenin also translocates to the cytosol where it cleaves non-coding RNA into RNA fragments, in particular transfer RNAs (tRNAs). Stress-induced tRNA fragments have been proposed to have multiple cellular functions, including inhibition of ribosome biogenesis, inhibition of protein translation and inhibition of apoptosis. We will discuss recent evidence of tRNA fragment accumulation in PD, as well as their potential neuroprotective activities.

Amyotrophic lateral sclerosis (ALS) presents a poorly understood pathogenesis. Evidence from patients and mutant SOD1 mouse models suggests vascular damage may precede or aggravate motor dysfunction in ALS. We have previously shown angiogenin (ANG) treatment enhances motor neuron survival, delays motor dysfunction and prevents vascular regression in the SOD1 G93A ALS model. However, the existence of vascular defects at different stages of disease progression remains to be established in other ALS models. Here, we assessed vascular integrity in vivo throughout different disease stages, and investigated whether ANG treatment reverses vascular regression and prolongs motor neuron survival in the FUS (1-359) mouse model of ALS. Lumbar spinal cord tissue was collected from FUS (1-359) and non-transgenic control mice at postnatal day (P)50, P90 and P120. We found a significant decrease in vascular network density in lumbar spinal cords from FUS (1-359) mice by day 90, at which point motor neuron numbers were unaffected. ANG treatment did not affect survival or counter vascular regression. Endogenous Ang1 and Vegf expression were unchanged at P50 and P90; however, we found a significant decrease in miRNA 126 at P50, indicating vascular integrity in FUS mice may be compromised via an alternative pathway. Our study demonstrates that vascular regression occurs before motor neuron degeneration in FUS (1-359) mice, and highlights that heterogeneity in responses to novel ALS therapeutics can already be detected in preclinical mouse models of ALS.This article has an associated First Person interview with the joint first authors of the paper., Competing Interests: Competing interestsJ.H.M.P. is a beneficiary of patents relating to the use of angiogenin for the treatment of CNS diseases., (© 2019. Published by The Company of Biologists Ltd.)