Manganese chelation therapy extends survival in a mouse model of M1000 prion disease

Abstract

J. Neurochem. (2010) 114, 440–451. Abstract Previous in vitro and in vivo investigations have suggested manganese (Mn2+) may play a role in pathogenesis through facilitating refolding of the normal cellular form of the prion protein into protease resistant, pathogenic isoforms (PrPSc), as well as the subsequent promotion of higher order aggregation of these abnormal conformers. To further explore the role of Mn2+ in pathogenesis, we undertook a number of studies, including an assessment of the disease modifying effects of chelation therapy in a well‐characterized mouse model of prion disease. The di‐sodium, calcium derivative of the chelator, cyclohexanediaminetetraacetic acid (Na2CaCDTA), was administered intraperitoneally to mice inoculated intra‐cerebrally with either high or low‐dose inocula, with treatment beginning early (shortly after inoculation) or late (at the usual mid‐survival point of untreated mice). Analyses by inductively coupled plasma‐mass spectrometry demonstrated brain Mn2+ levels were selectively reduced by up to 50% in treated mice compared with untreated controls, with copper, iron, zinc and cobalt levels unchanged. In mice administered high‐dose inocula, none of the treatment groups displayed an increase in survival although western blot analyses of early intensively treated mice showed reduced brain PrPSc levels; mice infected using low‐dose inocula however, showed a significant prolongation of survival (p = 0.002). Although our findings support a role for Mn2+ in prion disease, further studies are required to more precisely delineate the extent of pathogenic involvement.

FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice

“…1,2 For this reason, drug discovery for the prion diseases has focused primarily on compounds capable of inhibiting the conversion of PRNP. A number of drugs, including pentosan polysulfate (PPS), 3 quinacrine, 4 anti-PRNP antibodies 5,6 and others, 7,8 have been proposed as potential anti-prion agents. Most act by binding to PRNP C and inhibiting the interaction between PRNP C and PRNP Sc , resulting in a reduction of the conversion of PRNP C into PRNP Sc .…”

Prion infection in cells is abolished by a mutated manganese transporter but shows no relation to zinc

“…Also, cells incubated in higher levels of manganese in the medium are more susceptible to prion infection at lower titres . Other work has shown that treating infected mice with CDTA, a manganese chelator that causes efflux of manganese from the brain, results in a marked decrease of detectible PrP Sc in the brain (Brazier et al, 2010). Taken together these results strongly support the notion that the levels of PrP Sc in cells, and their propensity to be infected with prion disease are influenced by cellular concentrations of manganese.…”

“…Although copper can cause increased protease resistance, it has not been linked to the formation of PrP Sc (Quaglio et al, 2001;Roberts et al, 2013) but has been shown to accelerate its formation when PrP Sc is already present (McKenzie et al, 1998). In contrast, manganese has been suggested to cause spontaneous PrP Sc formation (Brown et al, 2000) and manganese chelation has been shown to decrease PrP Sc present in infected rodent brains (Brazier et al, 2010).…”

Manganese and Oxidative Stress

“…In agreement, a Mn chelator lengthens the incubation period of prion disease in mice, and reduces the amount of PrP present in their brains. 106 Despite these findings, the role of Mn in the pathogenesis of prion disease is currently unknown.…”