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Trail:
Science
Ultra Violet
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 Scientific
papers - Ultra Violet
Medical Hypotheses (2001) 57(1), 29-45
©2001 Harcourt Publishers Ltd doi: 10.1 054/mehy.2001.1305,
also available online at http://www.idealibrary.com
on
Does an ultra violet photo-oxidation of the manganese loaded copper
depleted
prion protein in the retina initiate the pathogenesis of TSE?
M. Purdey
Elworthy, Taunton, Somerset, UK.
Summary. Ecosystems supporting
clusters of sporadic transmissible spongiform encephalopathy (TSE)
are characterized by common properties of high-manganese/low-copper,
zinc, selenium mineral status, and highaltitude/snow-covered/pre-cambrian
mountain terrain where above-average intensities of ultra violet/ozone
oxidants are prevalent. Cell culture trials have confirmed the
hypothesis that manganese (Mn) substitutes at Prion Protein's (PrP's)
vacated copper (Cu) domain, whereupon PrP loses its Cu-mediated
antioxidant function, transforming into aprotease-resistant misfolded
isoform that aggregates into fibril 'tombstone' structures - the key
hallmark distinguishing TSE central nervous system (CNS) pathology. The
cellular localisation of PrP suggests PrP serves a 'front line'
contributory role in neutralizing radicals generated by incoming
environmental oxidants, whilst an intensive expression of PrP messenger
ribonucleic acid (mRNA) in the retina, melanocytes, epidermis, etc.,
suggests PrP performs a key antioxidant role as a 'photooxidative shock
absorber'; binding of porphyrin IX, Congo red and other photosensitisers
to PrPc suggests PrPc serves as an integral associate of the
porphyrin/melanin chromophore electron transfer chain; thereby
serving as a quencher of singlet O~superoxide generated by
photoenergised chromophores/xeno photosensitisers. It is proposed that
sporadic TSE pathogenesis is initiated in the retina of
environmentally/genetically predisposed individuals via a two-stage
chronic toxic process - Mn substitution at PrP's Cu domain forming a
stable Mn2+-PrP complex, followed by an ultra violet in situ
photo-oxidization of the Mn2+ component; whereby the latent 'Jekyll and
Hyde'capacity of thMn2+-PrP conjugate is activated into the fully
fledged, 'infectious' lethal autooxidizing, Mn3+-PrP 'prion'
agent. Thus, PrPc's Cu-mediated antioxidant function is replaced by a
Mn3+-mediated autooxidant dysfunction. Could the UK's increased loading
of a cocktail of environmental oxidants that penetrated the CNS of the
UK bovine (ultra violet microwaves/ozone/systemic cu-chelating
insecticides) account for a more virulent Mn4+ mediated acceleration of
the TSE degenerative process in Mn-contaminated/genetically predisposed
individuals, manifesting as the widespread emergence of new-variant
bovine spongiform encephalopathy (BSE), variant Creutzfeldt-Jacob
disease (vCJD)/FSE in younger mammals?
Received 20 December 2000, Accepted 9 January 2001
Mark Purdey - Correspondence by e-mail to: Mark
Purdey
INTRODUCTION
The conventional hypothesis on the origins of new variant (nv)/sporadic
TSEs considers that ingestion of TSE-infected CNS material (meat and
bone meal rations, bovinederived baby foods, scrapie-diseased sheep's
brain, etc.) is sufficient to initiate TSE in PrP-susceptible genotypes
(1p,2). However, the proponents of this theory do not address the fact
that significant tonnages of the 'nvTSE contaminated' foods which were
incriminated in the UK's BSE/nvCJD epidemics were exported worldwide to
bovine/human populations that remain free of nvTSE epidemics (3). Nor do
they address the fact that BSE has failed to emerge in various TSE-susceptible
species (e.g. sheep, goats) (1,2) who were fed the same TSE-incriminated
feed.
These flaws in the conventional theory (4) suggest that TSE-contaminated
feed could either play no role in TSE aetiology or it could play a
contributory role in conjunction with the genetic/environmental causal
prerequisites that are prevalent in the environments where TSE epidemics
erupt.
An alternative theory has evolved which expounds the possibility that
TSE pathogenesis is initiated in susceptible individuals who are
chronically exposed to a double- barrel' combination of specific
environmental properties that have been identified as common to TSE
cluster foci worldwide (4).
Whilst endorsing the mainstay of S. Prusiner's 'prion' hypothesis (2),
which heralds the conversion of a native nerve membrane glycoprotein,
prion protein (PrPc), into a misfolded, protease-resistant, 'infectious'
isoform (PrPsc) as integral to the development of TSE, this theory
extends Prusiner's concept by citing novel laboratory (5)/field trial
(4) data that amass a strong case for an 'environmental origin'
hypothesis as an explanation of the primary initiation of CNS PrP
conversion and the ensuing development of TSE.
A two stage toxic pathogenic mechanism
initiates TSE
A toxic template for TSE aetiology is proposed which is based upon
chronic exposure of susceptible individuals to environments which are
characterised by a high manganese (Mn)/low-copper (Cu), selenium (Se),
zinc (Zn) mineral status and above-average levels of photooxidative
/ozone-oxidative stress.
The putative pathogenic mechanism hinges upon a switch in PrPc's
molecular conformation, wherein PrPc loses its normal Cu-mediated
antioxidant function (6) and adopts a lethal prooxidant dysfunction.
This twostage pathogenic process primarily entails an abnormal Mn
substitution at the vacated Cu domain on PrP, causing PrP to misfold
into a stable protease resistant Mn2+PrP isoform (5), thereby losing its
specific Cu-mediated antioxidant function.
The second pathogenic step involves an in situ. ultra violet (or other
central nerve-penetrating environmental oxidant; ozone, systemic
insecticide, radio transponder collar/mobile phone, etc.) mediated
oxidization of the Mn component of the Mn2+-PrP conjugate in the
mitochondria; where the innocuous 'dormant' Mn2+-PrP complex is
activated into a lethal 'infectious" auto-oxidizing Mn3+/Mn4+-PrP
stable pathogenic agent (see Fig. 1).
The low levels of Se/Zn/Cu that have been found to characterize the TSE
cluster environments (4) would further predispose mammals that were
self-sufficient upon these foodchains to low-antioxidant activities of
the Cu/Zn-dependent superoxide dismutases (SODs)/catalases and
Se-dependent glutathione peroxidases (7,8), thus permitting the radical
chain reactions resulting from Mn3 +/Mn4+ -initiated autooxidation
(7,9,10) to proliferate out of control. Such auto-oxidizing initiated
cascades rapidly spread and envelop many of the mitochondria-rich
tissues/cell types of the CNS where Mn is highly concentrated (the
pituitary, pineal, basal ganglia, astrocyte cells, etc.) (11,12),
thereby subjecting surrounding membranes and tissues to the chaotic
pathogenic assault of lipid peroxidation and oxidative self-destruction
(7,8).
The two stage toxic pathway of sporadic TSE pathogenesis in the retina.
The two stage toxic pathway of new variant BSE pathogenesis in the
central nerves.
Fig. 1 The two stage toxic pathway of new variant BSE pathogenesis in
the central nerves.
The 'Jekyll and Hyde' redox status of
the Mn-prion conjugate
Mn 2+ normally exerts an important antioxidant function whilst harnessed
to the active site of the Mn SOD enzyme expressed in the lung, liver and
CNS (7). Mn can also exert abnormal prooxidant activity which is usually
associated with toxic CNS accumulations of Mn once the metal has been
oxidized into its trivalent Mn3+ oxidative species (9) - a situation
that is more prevalent in genotypes who are unable to express adequate
levels of Mn SOD activity.
In respect of the 'Jekyll and Hyde'-like redox status that pertains to
Mn within biological systems, the incorporation of Mn in the structure
of the melanin chromophore (10,13) may explain the mystery surrounding
this same alternating redox property of melanin and how this chromophore
can metamorphose into a potent generator of photoinduced oxygen species
that induces melanoma (14), having lost its normal protective function
as a quencher of photoinduced oxygen radical.
This theory ascribes a similar 'Jekyll and Hyde' property to PrP, where
TSE pathogenesis is initiated once the vacant Cu domain on PrP (15, 16)
has acquired an abnormal Mn3+/Mn4+ -mediated autooxidant malfunction
(7,9) having lost its normal Cu-mediated antioxidant function (6).
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