Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles

Huntington's; disease (HD), with its selective neuronal cell loss, is cause d by an elongated glutamine tract in the huntingtin protein, To discover th e pathways that are candidates for the protein's normal and/or abnormal fun ction, we surveyed 19 classes of organelle in Hdh(ex4/5)/Hdh(ex4/5) knock-o ut compared with wild-type embryonic stem cells to identify any that might be affected by huntingtin deficiency, Although the majority did not differ, dramatic changes in six classes revealed that huntingtin's function is ess ential for the normal nuclear (nucleoli, transcription factor-speckles) and perinuclear membrane (mitochondria, endoplasmic reticulum, Golgi and recyc ling endosomes) organelles and for proper regulation of the iron pathway. M oreover, upmodulation by deferoxamine mesylate implicates huntingtin as an iron-response protein, However, excess huntingtin produced abnormal organel les that resemble the deficiency phenotype, suggesting the importance of hu ntingtin level to the protein's normal pathway, Thus, organelles that requi re huntingtin to function suggest roles for the protein in RNA biogenesis, trafficking and iron homeostasis to be explored in HD pathogenesis.