Interplay between DYRK1A dosage and aneuploidy-induced neuropathology in Down syndrome

A reduction in the number of neurons and an increased susceptibility to apoptosis are one of the characteristic features observed in Down syndrome (DS). However, the multifaceted actions of chromosomal aneuploidy hinder the elucidation of the underlying mechanism. Here, using neurons and astrocytes differentiated from patient-derived induced pluripotent stem cells (iPSCs), we aimed to clarify the neuropathology of DS by focusing on aneuploidy-associated stress and the dosage effects of specific genes. Human chromosomal trisomies 13, 18, and 21 exert a stress response on neurons, resulting in the accumulation of protein aggregates. In addition, DYRK1A overdosage in trisomy 21 astrocytes causes intrinsic activation of the NLRP3 inflammasome, which leads to the release of inflammatory cytokines. These dual actions reciprocally interact and enhance neuronal apoptosis in trisomy 21. Notably, correction of DYRK1A copy number successfully rescued apoptotic neural death in combination with a chemical chaperone treatment. Our study provides insights into the neuropathological mechanism of DS and its potential therapeutic strategy.