Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells

Lengthening a glutamine tract in huntingtin confers a dominant attribute th at initiates degeneration of striatal neurons in Huntington's disease (HD). To identify pathways that ave candidates for the mutant protein's abnormal function, we compared striatal cell lines established from wild-type and H dh(Q111) knock-in embryos. Alternate versions of full-length huntingtin, di stinguished by epitope accessibility, were localized to different sets of n uclear and perinuclear organelles involved in RNA biogenesis and membrane t rafficking, However, mutant STHdh(Q111) cells also exhibited additional for ms of the full-length mutant protein and displayed dominant phenotypes that did not mirror phenotypes caused by either huntingtin deficiency or excess . These phenotypes; indicate a disruption of striatal cell homeostasis by t he mutant protein, via a mechanism that is separate front its normal activi ty. They also support specific stress pathways, including elevated p53, end oplasmic reticulum stress response and hypoxia, as potential players in HD.