Authors:

Louis Michael Delaby

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About Paper:

By 2080, individuals aged 65 and older are projected to outnumber children under 18 worldwide, raising concerns about age-related diseases like Alzheimer's disease (AD). These disorders are characterized by distinct molecular features, including transcriptional stress, genome instability, and chronic immune activation. Although these hallmarks of age-related pathologies are well documented, the underlying mechanisms driving these cellular changes remain largely unknown. Recent studies highlighted the role of R-loops, three-stranded nucleic acid structures composed of an RNA:DNA hybrid and a displaced single-stranded DNA, in contributing to age-related pathologies. These structures can trigger genomic instabilities by promoting transcription- replication conflicts and inducing double-strand breaks. DEAD-box RNA helicases, including DDX17 (Rm62 in Drosophila), are evolutionarily conserved proteins coordinating various aspects of RNA metabolism, including formation and resolution of R-loops, critical for maintaining gene expression. However, the role of DDX17/Rm62 in preserving genome stability and regulating transcription in aging and AD remains poorly understood. We utilized Drosophila melanogaster as a model organism due to its well-established use in studying age-related disorders and conservation of key molecular pathways with humans. Our findings demonstrate that reduced Rm62 levels resulted in global accumulation of R-loops. Transcriptome profiling using next-generation sequencing of Drosophila heads with reduced Rm62 levels identified widespread disruption in gene expression, including upregulation of genes involved in heat shock and immune responses. Overexpression of Rm62 rescued age-related declines in climbing ability. In a Drosophila model of Alzheimer's disease, reduction of Rm62 levels exacerbated the eye degeneration phenotype, suggesting a protective role for Rm62 in aging and age-related neurodegeneration. Keywords: R-loops; Rm62 Helicase; Aging; Gene Expression; Neurodegeration † Presenting Undergrad Author; ‡ Contributing Undergrad Author; * Undergrad Acknowledgment

Source:

Purdue University / 2025

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Co-authors:

Louis Michael Delaby