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Trail:
Ultra Violet
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Scientific
papers - Ultra Violet - page 2
The relationship between
Mn species and TSE 'strain' types
Mn substitution at PrPs Cu domain could represent the primary pathogenic
cornerstone that is fundamental to the aetiology of most 'strain' types
of TSE. Substitution could also occur with other hitherto unidentified
transition metals that are able to ligate at PrPs octapeptide Cu domain.
However, other TSE straintypes could develop following a range of
pathogenic scenarios that all result in a common disturbance at PrP's Cu
domain leading to a loss of PrP's Cu-mediated antioxidant function. One
such mechanism could involve a pollutant induced lipid peroxidation of
membranes, where the resulting peroxides interact at PrPs Cu2+ domain
initiating an 'in situ' fomation of hydroxyl/CU3+ radicals (7).
The specific strain type of TSE emerging at the end of the day is
dictated by the specific valency of the oxidized Mn species conjugated
to PrP, coupled to the PrP genotype (1,2) of the exposed individual. For
instance, Mn3+PrP could represent the causal agent responsible for
sporadic TSEs, whereas the more potent pro-oxidant Mn4+-PrP could
underlie the aetiology of nvTSEs.
These factors will influence key criteria that allow distinction between
the different strains of TSE, such as speed of incubation period, the
distribution of lesions in the CNS, etc. (17).
Mn bioaccumulation and the Mn-prion pyramid
The primary initiation event of this environmental hypothesis can
operate either singly or in conjunction with the consumption of TSE-contaminated
feeds; where first-stage initiation of the 'dormant' protease-resistant
Mrln2+-PrP complex can either be generated via an endogenous de novo
self-assembly in the CNS of susceptible genotypes who have been
chronically exposed to high-Mn/Low-Cu environments, or acquired via
ingestion (or vaccination) of an exogenous contaminant of feed derived
from Mn2+-PrP 'infected' CNS material; that Mn2+-PrP having been
generated and carried as 'dormant' within previous generations.
The model of a 'Mn-prion pyramid' (Fig. 2) is employed to depict the
increasing CNS concentrations of protease resistant Mn-prions which are
bioconcentrated up the farm animal food chain whenever practices of
cannibalistic consumption of prion-contaminated CNS material from
preceeding generations are implemented, e.g. in kuru (18) and BSE (2)
type TSEs.
Fig. 2. Manganese 3+ prion pyramid of bioconcentration in the
development of kuru tse in fore tribesfolk of Papua, New Guinea
following intake of volcanic Mn Oxide contaminants via local food/air
combined with cannibalistic ingestion of Mn rich CNS/pituitary tissues.
Recent trials by Collinge et al. (19) have demonstrated that prions can
exist in two forms in vivo: as an innocuous dormant form and as an
active TSE-generating form. This theory proposes that the introduction
of an exogenous oxidizing agent which oxidizes the Mn2+ component of the
dormant PrP complex into the lethal auto-oxidizing MW+-PrP complex,
provides a feasible candidate mechanism that can explain the insidious
transformation process operating between the two forms as well as its
relationship to the ultimate emergence of clinical TSE
EVIDENCE FOR A HIGH-Min/LOW-Cu, Se, Zn IN FOOD CHAINS OF TSE FOCI
Analyses of foodchains supporting high-incidence focal 'clusters' of
sporadic TSE (CJD in Slovakia, Calabria scrapie in N. Iceland and
Chronic Wasting disease (CWD in Colorado, USA) nv CJD in Queniborough,
Armthorpe has consistently demonstrated more than a 2.5 times higher
concentration of Mn in relation to levels recorded in adjoining TSE-free
localities (4). Likewise, levels of Cu, Zn and Se that serve as
antioxidant cofactors in biological systems were consistently classed as
very low in all the sporadic TSE regions studied (4).
The source of Mn contamination in these cluster zones originates from a
variety of natural (volcano) and industrial (steel, glass, munitions,
lead-free fuel, dye, etc.) manufacturing contexts where Mn had been
combusted into an oxide/silicate form and vented into the surrounding
environment as an airborn pollutant (4).
Interestingly, environments where certain types of Mn oxide mineral
(e.g. Lithiophorite) are naturally prevalent in the soil are also very
deficient in Cu/Zn/Co, because of the capacity of these Mn oxide
minerals to adsorb and conjugate with these trace elements (20). Such a
geochemical mechanism may elucidate the underlying basis for the
existence of this specific abnormal mineral configuration that has been
identified in TSE foodchains (4), and furthermore elucidate the
fundamental in vivo mechanism through which manganese oxide induces TSE
pathogenesis in the biological system.
Long-standing high-incidence clusters of TSE were selected for
analytical research where the respective TSE affected populations are
self-sufficient upon their local food chain (4). Evidence for the
presence of an environmental causal factor in TSE cluster zones is
demonstrated by the repeated failure of blanket slaughter regimes
executed for controlling animal TSEs across many of these zones
(22,1,2).
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