ATF3-dependent formation of inclusion bodies in polyQ-expressing human iPSC-derived neurons confers cellular protection [RNAseq]

While the causative mutation – CAG expansions within the coding region of the Huntingtin (HTT) gene – has been identified over 30 years ago, the pathological mechanisms underlying HD are still not clear. The abnormal CAG track encodes a polyglutamine (polyQ) expanded protein, which leads to HTT protein misfolding.

These polyQ aggregates can form insoluble inclusion bodies (IBs); however, whether IBs are protective or detrimental remains debatable. To ask whether IBs are protective or harmful in human neuronal cells, and to elucidate the pathological pathways involved in polyQ IB formation, we developed an iPSC-based human neuronal models for polyQ-related disorders. We ectopically expressed the first 21 exons of the HTT gene, containing either 18Q or 105Q fused with GFP in HD patient-derived iPSCs containing 180Q or their isogenic corrected cells, respectively, differentiated them into neuronal progenitor cells (NPCs), and enriched for a pure population of polyQ IBs-containing cells (IB+).