Fig. 1   The multifactorial aetiological template underpinning the pathogenesis of sporadic TSEs, where an Mn3+ initiated chain reaction of auto oxidation invokes a multi site radical attack on PrP and other CNS membrane/cytoskeletal proteins.

when PrP subsequently looses its correct conformation, ‘metamorphosing’ into a misfolded PrP-foreign transition metal complex, whereby Mn2+, or its oxidised Mn3+ species, serves as the ‘so called’ infectious transmissible agent whose potentially lethal auto-oxidative capacity (7,11) is carried along with PrP like a ‘trojan horse’ until the introduction of oxygen re-activates its latent oxidative capacity; whence Mn3+ initiates a more aggressive auto-oxidative cascade of free radical chain reaction, involving the auto-oxidation of dopamine, serotonin and adrenaline; it is recognised that Mn3+ readily oxidises these catecholamines (10,7,11) forming 6-hydroxy-dopamine, etc, which, in turn, oxidise more rapidly, forming quinines and superoxide/hydroxyl radicals which modify the catecholamine terminals, which could theoretically modify various amino acids on PrP and other membrane proteins. Such radical chain reactions would be prone to proliferate in mammals living in environments that are depleted in Cu, Fe, Zn, Se. Such deficiencies cause a down regulation in the turnover of the SOD, catalase, peroxidase and vitamin E scavengers (10).).
        The pathogenic scenario involving the cycling of the stable Mn2+ and Mn3+ species can be likened to the redox cycling of the paraquat herbicide molecule and its role in initiating a Parkinsons-like pathogenesis (10,13,14,16). Alternating double bonds and ‘resonance energy’ within paraquat provides a stable ‘dormant’ radical which auto oxidises once oxygen is introduced. After

reduction within the cell, it reacts with oxygen to generate the lethal superoxide radical (17).
        Mn is also recognised to activate some species of lectin, such as phytohemagglutinins and concanavalin A (4), where high levels of free Mn can accelerate the normal rate of concanavalin A interaction with cell surface glycoproteins, such as PrP. Interestingly, the action of concanavalin A and phytohemagglutins mediates a 3.5 fold increase in the surface abundance of PrP (18). Furthermore, increases in both the surface expression of PrP and CNS membrane receptor capping with concanavalin A are consistently recorded in the early stages of the TSE disease process (19), suggesting that an excess of available Mn in the CNS could putatively perform a key role (via lectin activation) in initiating these facets of TSE pathogenesis.
 
CU CHELATING CHEMICALS INDUCE
SPONGIFORM ENCEPHALOPATHIES
 
Cuprizone, neocuproine, mercaptoethanol, dithiophosphates and triethyltin are ‘true’ Cu chelating chemicals (20-22) which deplete Cu supplies in the CNS producing a ‘non-transmissible’, reversible type of spongiform encephalopathy. Cuprizone was actually utilised as a research tool for inducing a scrapie-like spongiosis in mice at Compton laboratories during the 1970s (23). CNS Cu deficiency could therefore represent one of the key prerequisites underlying TSE pathogenesis - albeit one which fails to account for the transmissible facet of TSEs.
        On the other hand, treatment with the ‘pseudo’ types of Cu chelating chemical such as diethyldithiocarbamate (DEDTC) (24) which chelate and redistribute Cu around the body rather than chelating and excreting it, do not produce spongiform encephalopathy (25); Allain et al. (24) treated rats with DEDTC which resulted in a 77% increase of Cu levels in the brain. Furthermore, DEDTC redistributes Cu into regions of the CNS that do not normally exhibit Cu binding ligands, thereby depositing free Cu in the extracellular space so it can initiate lipid peroxidation and chain reactions of hydroxyl and Cu 3 radical formation (10. Exposures to DEDTC and its parent compound sulfiram has been associated with the development of Parkinson’s disease and other extrapyramidal disorders (24, 26-28), supporting the proposal that CNS Cu deficiency rather than CNS Cu overloading is associated with TSE aetiology.
 
Is CNS Cu deficiency a prerequisite for TSEs?
 
Certain facets of TSE pathogenesis, such as tissue increase of Fe store, found as Ferritin (29), indicate a state of Cu/Fe deficiency.
        Furthermore, Lung tissues of copper deficient chicks have demonstrated abnormal variations in the concentration of various types of glycoaminoglycans (30). The possibility of an ‘in vivo’ metabolic relationship between PrP