Therapeutic implications of mutant huntingtin-induced dysregulation of brain iron homeostasis in a mouse model of Huntington's disease

Huntington's disease (HD) is caused by a polyglutamine repeat expansion within huntingtin protein. Elevated brain iron is reported in mouse and human HD though the mechanism through which mutant huntingtin promotes elevated brain iron and whether this contributes to disease progression is unknown. We characterized brain iron changes in the cerebral cortex and striatum of R6/2 HD transgenic mice. Increased total brain iron in HD mice at 8 weeks combined with increased non-heme iron at 12 weeks is consistent with a role for iron in HD progression. Alterations in iron homeostatic protein levels at 12 weeks alongside increased brain iron is consistent with a model of iron-induced cell stress promoting adaptive down-regulation of iron uptake and up-regulation of an iron export pathway. However, amyloid precursor protein ferroxidase activity, important for iron export from neurons, is decreased in striatum. Therefore, mutant huntingtin may promote iron accumulation by interaction with this protein.