Huntington's disease is caused by the expansion of CAG repeats in the HTT gene, resulting in selective neurodegeneration in the forebrain and eventually death; there is currently no cure or therapy to slow its onset. The link between the genetic causes and pathological outcomes, however, still remain unclear, as does the endogenous role of HTT in brain development and adult homeostasis. Now, Ali Brivanlou and colleagues describe a new tool to investigate these issues (dev156844): a series of isogenic human embryonic stem cell lines with graded increases in HTT CAG repeats in the endogenous locus. While these lines undergo neural induction in vitro and self-organise into neural rosettes, the rosettes are more disorganised, and cells within them show misaligned mitotic spindles. This disorganisation is accompanied by aberrant multinucleation, caused by a failure in abscission due to chromosomal instability. Intriguingly, phenotypes in the CAG repeat expansion lines are also observed in HTT knockout lines, arguing that CAG expansion mutations act as dominant negatives. This work adds to a body of literature suggesting a developmental, rather than solely homeostatic, contribution to Huntington's pathogenesis, and provides both cellular insight into its aetiology and a promising resource for further studies.
