MicroRNAs in polyglutamine diseases: Mechanistic insights, circulating biomarkers, and emerging microRNA-based therapeutic strategies.

Abstract

MicroRNAs (miRNAs) have emerged as critical regulators in the pathogenesis of polyglutamine (PolyQ) diseases-a group of fatal neurodegenerative disorders caused by CAG repeat expansions, such as Huntington's disease, spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and spinal and bulbar muscular atrophy. This review synthesizes recent advances in miRNA dysregulation across all nine PolyQ diseases, focusing on studies published since 2019. We examine how specific miRNAs modulate core pathogenic cascades-including mutant protein aggregation, transcriptional dysregulation, mitochondrial dysfunction, and apoptosis-and then link these molecular events to disease-relevant motor, cognitive, and psychiatric phenotypes. The review highlights therapeutic progress, including the preclinical efficacy of adeno-associated virus (AAV)-delivered artificial miRNAs and emerging exosome-based platforms that target mutant transcripts such as HTT, ATXN1, ATXN3, and ATXN7. AAV5-miHTT has advanced to a first-in-human trial for Huntington's disease (NCT04120493)-a key milestone in clinical translation. Circulating miRNAs in plasma and cerebrospinal fluid show diagnostic potential as minimally invasive, stage-specific biomarkers, but challenges persist in normalization, cross-biofluid concordance, and clinical validation. Despite substantial progress, translational barriers remain-including off-target effects, delivery optimization, immunogenicity, and patient heterogeneity. Overcoming these barriers will require integrative approaches that combine single-cell transcriptomics, engineered delivery systems, machine learning, and longitudinally phenotyped clinical cohorts. This review integrates mechanistic insights, biomarker discovery, and therapeutic development to move miRNA-based strategies toward disease-modifying interventions for PolyQ disorders.