Untwisted Sisters: Altered ADAR1 DNA-RNA coupling as a sex-specific driver of Alzheimer's Disease?
Speaker: Dr Paul Marshall
Group Leader
Division of Genome Sciences and Cancer
Australian National University
Untwisted Sisters:
Altered ADAR1 DNA-RNA coupling as a sex-specific driver of Alzheimer's Disease?
Abstract: Alzheimer's disease (AD) is more prevalent in women, yet the biological reasons for this remain poorly understood. Our work focuses on a molecular editing system — controlled by the protein ADAR1 — that normally keeps the brain's immune system in check. When functioning correctly, ADAR1 prevents the cell from mistaking its own genetic material for a viral threat, suppressing the kind of chronic inflammation increasingly recognised as central to AD pathogenesis.
Central to our model is Z-DNA — a rare, left-handed form of the DNA double helix that forms transiently at sites of active gene expression. Rather than being a genomic curiosity, we propose that Z-DNA acts as a structural docking platform that coordinates ADAR1's activity between the nucleus and cytoplasm. When this structural signal is disrupted, we hypothesise that the coupling between nuclear gene regulation and cytoplasmic immune suppression breaks down — leaving the brain vulnerable to runaway inflammation.
Using post-mortem human brain tissue stratified by sex and disease state, we are mapping how Z-DNA architecture and ADAR1-mediated editing are coordinately altered in AD. Strikingly, our pilot data reveal that the pattern of Z-DNA disruption differs between male and female brains, pointing toward a sex-specific molecular mechanism that could help explain the unequal burden of AD.
If confirmed, this Z-DNA–ADAR1 axis may represent a new class of therapeutic targets — and a new lens through which to understand why Alzheimer's disease affects women so disproportionately.
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