Fig 6. Hypothesized biological cascade related to increased micronuclei frequencies in cells with a trisomy 21 imbalance.

Micronuclei can arise from a variety of mechanisms, including (but not limited to) factors that arise during mitosis (top of figure) (Guo et al., 2019). Due to nuclear envelope (NE) pores/gaps or rupture, micronuclei can be perceived as “cytoplasmic” DNA, triggering the cGAS-cGAMP-STING pathway, which in turn leads to the production of interferons. This “mark” targets the cells for senescence, the latter of which also contribute to inflammation (via SASP), thereby perpetuating the CIN-inflammation cycle. The micronuclei, either directly via genetic imbalance, or indirectly via inflammation and/or senescence, can contribute to alterations in gene expression. In turn, these alterations could contribute to the acquisition of age-related health conditions in people with Down syndrome or mosaic Down syndrome, but this conjectured relationship is not yet proven (as indicated by the?). SAC = Spindle Assembly Checkpoint; NE = Nuclear Envelope; ROS = reactive oxidative stress; SASP = Senescence Associated Secretory Phenotype.