Circular RNAs in amyotrophic lateral sclerosis.

Gene expression in amyotrophic lateral sclerosis: an integrative narrative review of microarray findings, pathogenic mechanisms, and technical challenges

Abstract Amyotrophic Lateral Sclerosis (ALS) is a devastating and progressive neurodegenerative disorder with a complex and multifactorial pathogenesis characterized by the loss of upper and lower motor neurons. Despite advances in molecular biology, its pathogenesis remains incompletely understood. This narrative review synthesizes findings from key microarray studies, focusing on dysregulated pathways such as ribosomal function, protein synthesis, and metabolic processes within motor nerves and Schwann cells. We further explore the emerging role of competitive endogenous RNA (ceRNA) networks, particularly those involving long non-coding RNAs (lncRNAs), as revealed by advanced bioinformatics in Alzheimer's disease research. Drawing on this conceptual framework, we discuss how similar regulatory mechanisms might operate in ALS, identifying this as a promising direction for future investigation rather than an established finding. A critical analysis of the technical limitations of microarrays—including small sample sizes, the curse of dimensionality, and challenges in validation—is presented. Finally, we discuss future perspectives, advocating for the integration of microarray data with multi-omics approaches, the application of sophisticated machine learning and deep learning techniques, and the use of distributed computing to overcome current analytical bottlenecks. This integrative approach aims to bridge molecular discoveries with methodological advancements, fostering a deeper understanding of ALS pathogenesis and highlighting novel therapeutic targets.

Transcriptional pathways of definitive ALS genes implicate novel disease-associated target genes

This work identifies transcriptional pathways linking variants in definitive ALS genes to widespread coordinated co-expression activity driven by gene-specific transcriptional programs, and establishes a generalizable framework that is readily applicable across heritable diseases for the identification of disease-relevant molecular pathways and target genes.

Lesion-specific circular RNA and mRNA signatures in secondary progressive multiple sclerosis

Circular RNAs (circRNAs) are single-stranded RNAs with a covalently closed loop structure which have been increasingly recognised as stable and functionally relevant regulators of gene expression via sponging miRNAs. Recently, studies have revealed their roles in human diseases, subsequently emerging as potential biomarkers. Multiple sclerosis (MS) is an inflammatory, neurodegenerative, and immune-related disease of the central nervous system characterised by distinct lesion types that reflect different stages of brain tissue injury and repair. Our study conducted a comprehensive transcriptomic analysis of circRNAs and linear mRNAs across secondary progressive MS (SPMS) lesion types, including normal-appearing white matter, active lesions, chronic active lesions, inactive lesions, and control white matter tissue. Using RNA-seq data and bioinformatics-based analysis, we identified lesion-specific circRNAs and linear transcripts signatures and visualised their expression patterns across samples using row-scaled heatmaps. Functional enrichment analysis revealed that dysregulated circRNAs were associated with synaptic organisation, intracellular signalling, immune responses, and chromatin regulation. To explore potential regulatory mechanisms, we constructed hub genes networks for circQSER1-hsa-miR-6891-5p/hsa-miR-6758-5p- SCD , circFMN2-hsa-miR-4728-5p- SCD axes from down-regulated active lesion type, circCCDC7-hsa-miR-4659b-3p- HBEGF axes from chronic active lesion type for circRNA-miRNA-mRNA. Detailed visualisation of the circRNAs that were identified to be involved in the axes demonstrated extensive isoform diversity and circularisation events within key loci. Our results highlight that circRNAs-associated networks exhibit lesion-specific expression and structural diversity in SPMS and may participate in MS-associated biological processes. This study provides a deeper understanding of circRNAs dysregulation across lesion types and uncovers potential candidate targets and candidate regulatory axes.

RNA Splicing Dysregulation in Parkinson’s Disease

Current evidence on the RNA regulatory networks in PD is examined, highlighting the role of transcript isoforms and RBPs in neuronal dysfunction and emerging data suggest that dysregulation of RNA binding proteins (RBPs) may influence RNA processing in PD.

Targeting TDP-43 in sporadic amyotrophic lateral sclerosis

A replicated astrocyte long non-coding RNA signature of Alzheimer's disease is inverted in amyotrophic lateral sclerosis.

Reactive astrocyte transitions are central to neurological disease, yet their long non-coding RNA (lncRNA) regulators remain poorly defined, and single-nucleus studies frequently treat nuclei rather than donors as replicates. This study analyses publicly available human single-nucleus RNA sequencing from four disorders using donors as the unit of inference throughout: Alzheimer's disease (AD; middle temporal gyrus, 88 donors), C9orf72-associated amyotrophic lateral sclerosis and ALS/frontotemporal dementia (ALS; frontal cortex), multiple sclerosis (MS; cortex and white matter), and major depressive disorder (MDD; amygdala). The public MDD release pools nuclei by condition, so that arm cannot support donor-level inference and is exploratory only. Covariate-adjusted pseudobulk analysis of 70,009 CE astrocytes, controlling for sex, age at death and assay chemistry, identified 1,019 down-regulated autosomal lncRNAs after sex-chromosome transcripts were removed. This signature was not attributable to astrocyte subtype composition, which did not differ between groups, and 99.9% of members remained down-regulated within the dominant homeostatic subtype alone. The signature replicated in an independent AD cohort (32 of 41 testable members concordant; resampling P < 0.0001). Testing it outside AD gave a directional result: it was concordant in the MS discovery cohort (P < 0.0001) but inconclusive in an independent MS cohort in which the transcripts lay near the detection floor, and it was reproducibly inverted in ALS, in the C9orf72 discovery cohort and in an independent motor-cortex cohort not restricted to C9orf72 carriers. The inversion survived negative controls for global normalisation and expression level. These astrocyte lncRNA changes are therefore disorder-specific rather than pan-neuroinflammatory.