We propose that neural damage in Parkinson's disease (PD) is due to dysregulation of iron utilization rather than to high iron levels per se. Iron deposits are associated with neuronal cell death in substantia nigra (SN) resulting in PD where high levels of iron in SNs are due to dysregulation of iron utilization. Cytosolic aconitase (ACO1) upon losing an iron-sulfur cluster becomes iron regulatory protein 1 (IRP1). Rotenone increases levels of IRP1 and induces PD in rats. An increase in iron leads to inactivation of IRP1. We propose a novel treatment strategy to prevent PD. Specifically in rats given rotenone by subcutaneous injections, iron, from iron carbonyl from which iron is slowly absorbed, given three times a day by gavage will keep iron levels constant in the gut whereby iron levels and iron utilization systematically can be tightly regulated. Rotenone adversely affects complex 1 iron-sulfur proteins. Iron supplementation will increase iron-sulfur cluster formation switching IRP1 to ACO1. With IRP1 levels kept constantly low, iron utilization will systematically be tightly regulated stopping dysregulation of complex 1 and the neural damage done by rotenone preventing PD.
Keywords: Parkinson’s disease (PD); aconitase 1 (ACO1); cystine/glutamate antiporter; ferroptosis; iron dysregulation; iron regulatory protein 1 (IRP1); treatment strategy.