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Abstract
Objective biomarkers for the clinically heterogeneous adult-onset neurodegenerative disorder amyotrophic lateral sclerosis are crucial to facilitate assessing emerging therapeutics and improve the diagnostic pathway in what is a clinically heterogeneous syndrome. With non-coding RNA transcripts including microRNA, piwi-RNA and transfer RNA present in human biofluids, we sought to identify whether non-coding RNA in serum could be biomarkers for amyotrophic lateral sclerosis. Serum samples from our Oxford Study for Biomarkers in motor neurone disease/amyotrophic lateral sclerosis discovery cohort of amyotrophic lateral sclerosis patients (n = 48), disease mimics (n = 16) and age- and sex-matched healthy controls (n = 24) were profiled for non-coding RNA expression using RNA-sequencing, which showed a wide range of non-coding RNA to be dysregulated. We confirmed significant alterations with reverse transcription-quantitative PCR in the expression of hsa-miR-16-5p, hsa-miR-21-5p, hsa-miR-92a-3p, hsa-piR-33151, TRV-AAC4-1.1 and TRA-AGC6-1.1. Furthermore, hsa-miR-206, a previously identified amyotrophic lateral sclerosis biomarker, showed a binary-like pattern of expression in our samples. Using the expression of these non-coding RNA, we were able to discriminate amyotrophic lateral sclerosis samples from healthy controls in our discovery cohort using a random forest analysis with 93.7% accuracy with promise in predicting progression rate of patients. Importantly, cross-validation of this novel signature using a new geographically distinct cohort of samples from the United Kingdom and Germany with both amyotrophic lateral sclerosis and control samples (n = 156) yielded an accuracy of 73.9%. The high prediction accuracy of this non-coding RNA-based biomarker signature, even across heterogeneous cohorts, demonstrates the strength of our approach as a novel platform to identify and stratify amyotrophic lateral sclerosis patients.
Highlights
The majority of those with the adult-onset neurodegeneration amyotrophic lateral sclerosis (ALS) typically develop a syndrome of rapidly progressive muscle weakness secondary to motor neuronal loss, resulting in death within 3 years of first symptoms, typically from ventilatory insufficiency (Kiernan et al, 2011)
Several other non-coding RNA species (ncRNA) species are present in serum including ribosomal RNA and transfer RNA which have been used as potential biomarkers in other diseases (Liao et al, 2010; Cheng et al, 2014; Lopez et al, 2015; Iliev et al, 2016; Umu et al, 2018; Yoffe et al, 2018)
Using Illumina-based RNA-seq, 3,438,537 reads per pooled sample on average were generated, which we analysed using two different approaches: the Qiagen automated analysis (QA) and an optimized open-sourced software-based workflow hosted on the Galaxy web servers (GA)
Summary
The majority of those with the adult-onset neurodegeneration amyotrophic lateral sclerosis (ALS) typically develop a syndrome of rapidly progressive muscle weakness secondary to motor neuronal loss, resulting in death within 3 years of first symptoms, typically from ventilatory insufficiency (Kiernan et al, 2011). Several other ncRNA species are present in serum including ribosomal RNA (rRNA) and transfer RNA (tRNA) which have been used as potential biomarkers in other diseases (Liao et al, 2010; Cheng et al, 2014; Lopez et al, 2015; Iliev et al, 2016; Umu et al, 2018; Yoffe et al, 2018) Efficient investigation of these ncRNA requires the use of RNA-seq, and to date only one study has detected ncRNA in ALS biofluid samples, though they did not further consider these as biomarkers (Matamala et al, 2018). We hypothesized that multiple ncRNAs are dysregulated in ALS, potentially reflecting key aspects of the syndrome’s
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