Prion diseases and manganism

Abstract

Recent studies on mice experimentally infected with scrapie suggested that large increase in the levels of manganese ion occurs in blood and brain prior to the onset of symptoms of the prion disease, and the observed elevated manganese ion in several central nervous systems implies that the prion diseases should be considered to be one of the manganism. We have observed that oxidation of Mn(III) ion in several manganese chelates occurs in the presence of apo-transferrin, giving a di-μ-oxo bridged Mn(III/IV) species (hereafter we will call these Mn(III) and Mn(IV) ions to be labile plasma manganese ions), and at the same time facile uptake of manganese ions by apo-transferrin proceeds. This clearly shows that most manganese ions can be transported to the brain in a facile manner by transferrin under certain conditions. There are many iron-containing enzymes in the brain, and substitution of iron ion in these enzymes with other metal ions such as manganese ion results in complete or partial loss of enzymatic activity, and this is because the reactivity of the iron ion towards oxygen molecule is quite different from that of the manganese ions. Thus, the excess accumulation of the manganese ion in the brain should lead to (a) abnormality in iron metabolism, i.e., the increase of the labile plasma iron (or non-transferrin-bound iron, NTBI), which is in fact observed for the certain regions of the brain of scrapie strain infected mice; these iron ions are not transferred to transferrin, giving to the iron-deficiency state in the brain which leads to the defect of neurotransmitters such as dopamine and serotonin and (b) the abnormalities of the brain functions due to the toxicity of the labile plasma iron ions, which leads to neural cell death. Based on the above facts, and that (1) the labile plasma iron can in a facile manner produce the hydrogen peroxide and (2) the prion diseases can be elucidated by the “gain-of-function” of the prion proteins as copper(II)-containing enzyme in the presence of excess hydrogen peroxide, we have concluded that the prion diseases including both the sporadic and infected types should be elucidated by the combined toxicities due to the both labile plasma manganese and iron ions. Very recently we have succeeded in obtaining the chelate which captures both the labile plasma iron and manganese ions effectively and removes these ions without toxicity from the solution in vitro. Thus, we can hope that our new chelates should make notable contribution to the prevention and therapeutics for the prion disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, schizophrenia, and dementia, which are now in progress in Japan.