A mouse model of hemochromatosis-related mutations with brain iron dyshomeostasis exhibits loss of tyrosine hydroxylase expression in dopaminergic neurons and motor control impairment relevant to Parkinson's disease

UK Biobank studies show Parkinsons disease risk is almost doubled in men homozygous for the homeostatic iron regulator gene HFE p.C282Y polymorphism, associated with the common genetic iron disorder hemochromatosis. Whether this relationship is causal or spurious is unknown. We previously reported a novel Hfe-/-xTfr2mut mouse model of hemochromatosis with elevated brain iron ([~]1.5-1.8x). We now show these mice have reduced substantia nigra tyrosine hydroxylase expression at 3 months and 9 months age, sometimes exhibit severe hindlimb clasping by 7-8 months, have impaired rotarod and balance beam performance at 9 months and are untestable on the pole test. These parkinsonian features place the model at the forefront of genetic mouse models of PD, which generally do not show both TH loss and motor impairment. This confirms hemochromatosis-related mutations can cause parkinsonian features, substantiating causality of epidemiological relationships. Despite total brain iron elevation, neuronal iron remains low in Hfe-/-xTfr2mut mice, consistent with hemochromatosis-related mutations disrupting the normal, iron-responsive regulation of the neuronal iron exporter ferroportin by hepcidin. Parkinsonian features may reflect reduced mitochondrial respiratory complex (MRC) activity due to functional neuronal iron depletion. This may be exacerbated by indiscriminate chelation and could instead respond to drugs targeting the hepcidin-ferroportin axis or MRC activity. This new model of chronic parkinsonism that increases with age provides unprecedented insights into the complex relationships of brain iron regulation and movement impairment. Since parkinsonism of diverse etiologies can exhibit iron dysregulation, the model may facilitate pre-clinical to end-stage studies relevant to both sporadic and genetic PD.