I will discuss juvenile and infantile forms of human pluripotent stem cell (hPSC) isogenic models for Huntington’s disease (HD), the most common poly-glutamine (polyQ) related disorder. HD is caused by CAG (encoding glutamine, Q) expansions within the Huntingtin (HTT) gene. The aberrant polyQ-containing protein cannot fold properly, ultimately leading to the formation of polyQ aggregates within mutant cells. While HD is a late-onset neurodegenerative disease, we find that brain organoids derived from hPSCs show widespread DNA demethylation and an increased ‘epigenetic age’. Mechanistically, we identified increased interaction between the de novo DNA methytransferase DNMT3B and mutant HTT. Comparing hPSCs-derived neuronal progenitor cells (NPCs) with and without polyQ aggregates, we revealed specific pathways including neuroinflammation, and identified the transcription factor ATF3 as responsible for the induction of neuroinflammation genes in aggregate-containing cells. Remarkably, we find that cells in which aggregates are formed are more resistant than similar cells devoid of aggregates, suggesting that polyQ aggregates may be protective rather than harmful. Finally, an HD mouse model lacking ATF3 (R6/1-ATF3-/-) which we generated shows exacerbated HD-related phenotypes compared with R6/1-ATF+/+ littermates.

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