It will be interesting to explore whether eccDNA tethering to NPC structures is also a mechanism to modulate eccDNA load in mammalian cells (Table 1) and to define the impact of its deregulation on the development of diseases, which implicate disturbed NPC-associated functions, such as evidenced for C9ORF72-related amyotrophic lateral sclerosis (ALS) [100,101,102]. The gene discussed is C9orf72; the disease is amyotrophic lateral sclerosis.