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Still unresolved is the question of how a lifetime accumulation of somatic gene copy number alterations impact organ functionality and aging and age-related pathologies. Such an issue appears particularly relevant in the broadly post-mitotic central nervous system (CNS), where non-replicative neurons are restricted in DNA-repair choices and are prone to accumulate DNA damage, as they remain unreplaced over a lifetime. Both DNA injuries and consecutive DNA-repair strategies are processes that can evoke extrachromosomal circular DNA species, apparently from either part of the genome. Due to their capacity to amplify gene copies and related transcripts, the individual cellular load of extrachromosomal circular DNAs will contribute to a dynamic pool of additional coding and regulatory chromatin elements. Analogous to tumor tissues, where the mosaicism of circular DNAs plays a well-characterized role in oncogene plasticity and drug resistance, we suggest involvement of the “circulome” also in the CNS. Accordingly, we summarize current knowledge on the molecular biogenesis, homeostasis and gene regulatory impacts of circular extrachromosomal DNA and propose, in light of recent discoveries, a critical role in CNS aging and neurodegeneration. Future studies will elucidate the influence of individual extrachromosomal DNA species according to their sequence complexity and regional distribution or cell-type-specific abundance.

Extrachromosomal Circular DNA: Current Knowledge and Implications for CNS Aging and Neurodegeneration