Numerous lines of evidence suggest that DNA damage contributes to the initiation, progression, and severity of neurodegenerative diseases. However, the molecular mechanisms responsible for this relationship remain unclear. This review integrates historical data with contemporary findings to propose that DNA damage exacerbates neurodegenerative diseases by inducing transcription errors. First, we describe the scientific rationale and basic biological concepts that underpin this hypothesis. Then, we provide epidemiological, cellular, and molecular data to support this idea, and we describe new and recently published observations that suggest that the former high incidence of neurodegenerative disease in Guam may have been driven by DNA damage-induced transcription errors. Finally, we explore the long-term implications of these findings on our understanding of the impact of genotoxic stress on human aging and disease.
Keywords: DNA damage; mutagenesis; mutant proteins; neurodegenerative diseases; protein aggregation; transcription errors.