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RNA sequencing of peripheral blood in amyotrophic lateral sclerosis reveals distinct molecular subtypes: considerations for biomarker discovery

ABSTRACT: Aim: Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease with limited therapeutic options. A key factor limiting the development of effective therapeutics is the lack of disease biomarkers. We sought to assess whether biomarkers for diagnosis, prognosis or cohort stratification could be identified by RNA sequencing (RNA-seq) of ALS patient peripheral blood. Methods: Whole blood RNA-seq data were generated for 96 Australian sporadic ALS (sALS) cases and 48 healthy controls (NCBI GEO accession GSE234297). Differences in sALS-control gene expression, transcript usage and predicted leukocyte proportions were assessed, with pathway analysis used to predict the activity state of biological processes. Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning algorithms were applied to search for diagnostic and prognostic gene expression patterns. Unsupervised clustering analysis was employed to determine whether sALS patient subgroups could be detected. Results: 245 differentially expressed genes were identified in sALS patients relative to controls, with enrichment of immune, metabolic and stress related pathways. sALS patients also demonstrated switches in transcript usage across a small set of genes. We established a classification model that distinguished sALS from controls with an accuracy of 78% (sensitivity: 79%, specificity: 75%) using the expression of 20 genes. Clustering analysis identified four patient subgroups with gene expression signatures and immune cell proportions reflective of distinct peripheral effects. Conclusions: Our findings suggest that peripheral blood RNA-seq can identify diagnostic biomarkers and distinguish molecular subtypes of sALS patients however, its prognostic value requires further investigation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234297 | GEO | 2023/10/12

REPOSITORIES: GEO

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Project description:Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis and serving as biomarkers of amyotrophic lateral sclerosis (ALS). Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and CSF (cEVs) of sporadic ALS (SALS) patients remain unexplored. This study sought to reveal such changes by collecting serum and CSF at fixed intervals from 10 controls and 20 SALS patients participating in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis trial. We also aimed to reveal longitudinal changes with disease progression and the effects of ropinirole hydrochloride (ROPI, a dopamine D2 receptor agonist identified as an anti-ALS drug candidate using induced pluripotent stem cell drug discovery) on protein profiles of EVs. Comprehensive proteomic analyses of EVs extracted from these samples were conducted using liquid chromatography-mass spectrometry to trace longitudinal shifts linked to disease progression and the influence of ROPI on EV protein profiles. The findings revealed notable disparities but high congruity in sEV and cEV protein profiles concerning disease status, time, and ROPI administration. Moreover, the sEV and cEV protein profiles converged over time in SALS patients, at least in part, suggestive of a loosening of the blood–brain barrier. In SALS patients, both sEVs and cEVs presented elevated inflammation-related protein levels but reduced levels of proteins associated with the unfolded protein response. These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to the unfolded protein response in SALS, suggesting an anti-ALS effect on EV protein profiles. Reverse translational research using induced pluripotent stem cell-derived astrocytes indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. Baseline levels of OGN in sEVs and FRMPD1 in cEVs correlated with subsequent disease progression, indicating their potential as prognostic biomarkers for SALS. Machine learning-driven biomarker searches and diagnostic classification yielded an accuracy of 90.4% for sEVs and 80.3% for cEVs. Despite the limited sample size, this study is the first to report time-series proteomic alterations in sEVs and cEVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.

Project description:Knowledge about the nature and timepoint of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis (ALS) is largely lacking. It could not only pave the way for valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs (miRNAs) are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained expression profiles of miRNAs as well as other non-coding RNAs (ncRNAs) in the serum of sporadic ALS patients (sALS), familial ALS cases (fALS), asymptomatic mutation carriers and healthy controls. We observed a strikingly homogenous ncRNA profile in fALS patients that, to a large extend, was independent to the underlying disease gene and different to heterogeneous ncRNA signatures in sALS patients. Moreover, we identified 68 significantly dysregulated ncRNAs in pre-manifest ALS mutation carriers, more than 20 years before the estimated time window of disease onset. 91% of ncRNA alterations in mutation carriers overlapped with the fALS patients revealing progressive changes towards and during the disease. Our data thus demonstrate a high epigenetic heterogeneity amongst sALS patients and suggest common denominators regarding molecular pathogenesis of different ALS genes. We describe the earliest pathomolecular alterations in ALS known to date, which provide a basis for the development of predictors of disease onset as well as the discovery of novel therapeutic targets and strongly argue for studies evaluating pre-symptomatic disease-modifying treatment in ALS. Serum ncRNA pofiles of sporadic and familiar ALS patients as well as asymptomatic ALS mutation carriers were compared to age and gender matched healthy controls using a total of 53 Affymetrix miRNA 3.0 arrays. In detail, a total of 9 fALS patients (analyzed in 6 arrays) were compared to 10 controls, a total of 18 ALS mutation carriers (analyzed in 12 arrays) were compared to 8 controls and 18 sALS patients were compared to 16 controls.

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RNA sequencing of peripheral blood in amyotrophic lateral sclerosis reveals distinct molecular subtypes: considerations for biomarker discovery

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