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Trail:
Science
Ecosystems
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 Scientific
papers - Ecosystems
Medical
Hypotheses (2000) 54(2), 278-306
© 2000 Harcourt Publishers Ltd
DOI: 10.1054/mehy.1999.0836, available online at http://www.idealibrary.com
on
Ecosystems supporting
clusters of sporadic TSEs demonstrate excesses of the radical-generating
divalent cation manganese and deficiencies of antioxidant co factors Cu,
Se, Fe, Zn
Does a foreign cation
substitution at prion protein's Cu domain initiate TSE?
M. Purdey -Taunton,UK
Summary Analyses
of food chains supporting isolated clusters of sporadic TSEs (CWD in N
Colorado, scrapie in Iceland, CJD in Slovakia) demonstrate a consistent
2 1/2 + fold greater concentration of the pro-oxidant divalent cation,
manganese (Mn), in relation to normal levels recorded in adjoining TSE-free
localities. Deficiencies of the antioxidant co factors Cu/Se/Zn/Fe and
Mg, P and Na were also consistently recorded in TSE foodchains.
Similarities between the clinical/pathological profile of TSEs and Mn
delayed psycho-neurotoxicity in miners are cited, and a novel theory
generated which suggests that sporadic TSE results from early life
dependence of TSE susceptible genotypes on ecosystems characterised by
this specific pattern of mineral imbalance. Low Cu/Fe induces an
excessive absorption of Mn in ruminants and an increased oxidation of
Mn2+ into its pro oxidant species, Mn3+, which accumulates in
mitochondria of CNS astrocytes in Mn SOD deficient genotypes.
Deficiencies of scavenger co factors Cu/Zn/Se/Fe in the CNS permits Mn3+
initiated chain reactions of auto-oxidant mediated neuronal degeneration
to proliferate, which, in turn, up-regulates the expression of the Cu-metalloprotein,
prion protein (PrP). Once the rate of PrP turnover and its demand for Cu
exceeds the already depleted supply of Cu within the CNS, PrP can no
longer bind sufficient Cu to maintain its conformation. Mn3+ substitutes
at the vacated Cu domain on PrP thus priming up a latent capacity for
lethal auto-oxidative activity to be carried along with PrP like a 'trojan
horse'; where Mn3+ serves as the integral 'infectious' transmissible
component of the misfolded PrP -cation complex. The Mn overactivation of
concanavalin A binding to glycoprotein and Mn-initiated autoxidation
results in a diverse pathological profile involving receptor capping,
aggregation/modification of CNS membrane/cytoskeletal proteins. TSE
ensues. The BSE/nv CJD strain entails a 'synthetic' induction of the
same CNS mineral disturbance, where 'in utero' exposure to Cu-chelating
insecticides/Mn supplements accelerates the onset of a more virulent
'strain' of adolescent TSE. ©
2000 Harcourt Publishers Ltd
Received
1 April 1998 Accepted 29 October 1998
INTRODUCTION
It has been previously suggested that high levels of cation
metals such a manganese may interact with the CNS prion protein
(PrP) and play a role in the pathogenesis of sporadic forms of
transmissible spongiform encephalopathy (TSE) (1,2).
Analyses of ecosystems supporting isolated, well defined
clusters of sporadic TSE in Iceland, Colorado and Slovakia
demonstrate high concentrations of the free radical generating
divalent cation, manganese (Mn), as well as marked deficiencies
of the radical scavenger enzyme cofactors; Cu, Zn, Fe, Se and
the elements Mg/P/Na. The findings of high levels of Mn in TSE
ecosystems may not necessarily indicate any direct relationship
between Mn overloading and the aetiology of TSE. It could merely
reflect some indirect association between the two; eg, where a
further 'third party' common environmental factor which promotes
the accumulation of Mn in plant material may also promote the
survival of 'agent X' which causes TSE.
However, various other research studies indicate that the
results of this survey may indeed demonstrate a direct
aetiological association between Mn exposure and TSEs. For
instance, close similarities exist between the
pathological/clinical profile of TSEs and the Mn induced delayed
psycho-neurodegenerative syndrome found in Mn miners (3,4) where
the key idiosyncratic CNS pathological features of TSE (5), such
as the presence of amyloid plaques and fibrils, are common to
both conditions (6). Furthermore, 1999 pilot studies conducted
by Dr David Brown of the Dept of Biochemistry, Cambridge
University, UK, have demonstrated that the divalent cations, Mn
and Nickel, will both bind to recombinant PfP and refold the
protein into a protease resistant, misfolded isoform.
Protease-resistant PrP represents the foremost key feature that
hallmarks the pathology of TSE diseased brain (5).
A novel aetiological
hypothesis for TSEs is compiled from the data amassed in this
pioneer study of TSE ecosystems. It proposes that the trivalent
species of Mn cation serves as the all important 'infectious'
transmissible agent in TSEs.
Mn is a divalent cation, and, much like other divalent species such as Cu and Fe,
Mn can perform a dual role in biological systems; as a pro
oxidant when freely 'available' at high concentrations and as an
antioxidant when conjugated onto its respective scavenger
enzyme, Mn superoxide dismutase (Mn SOD) (3,4). During the
resting stages of the enzymic cycle, MnSOD acts as a safe
'depot' for Mn3+, thus protecting tissues against the potential
onslaught of its pro-oxidant activities (3,4).
It is proposed that
sporadic TSEs with develop in defective MnSOD/PrP genotypes who
are chronically dependent on foodchains that are characterised
by two abnormal coexisting factors; high levels of the divalent
cation Mn and deficiencies of other metals Cu/Zn/Fe/Se which
serve as scavenger enzyme co factors in biological systems.(NB;
Cu, Fe and P deficiencies in the external food chain would also
promote the excessive absorption of Mn across the gut barrier
(3,4).
Cu deficient
ecosystems generally conform to a seasonal Cu cycle that is
characterised by a ten month period of Cu-starvation in
vegetation, followed by an ephemeral 20 fold burst of Cu
availability during August (8), which, in turn, mediates an
ephemeral rise in levels of the Cu-glycoprotein 'ceruloplasmin'
in mammals thriving off these foodchains (8). Such an abrupt
increase in ceruloplasmin turn over could subsequently oxidise a
greater proportion of the excess of Mn2+ into its lethal Mn3+
species (7) - particularly likely to occur in ecosystems
deficient in ceruloplasmin's normal oxidative target, Fe2+.
Mn2+/Mn3+ are recognized to concentrate exclusively within the
CNS during contexts of Mn overloading (7), where excesses of
'available' Mn2+/Mn3+ can persist for up to a year (7). CNS Mn
accumulation can result from intranasal intake of airborn
concentrations of Mn transported via the olfactory neurones (9)
as well as in the gastrointestinal route (3,4,7). Genotypes
deficient in MnSOD activity would be less able to provide 'sink'
storage for the excess of Mn, and would therefore be more
susceptible to the ravages of Mn3+ induced chain reactions of
oxidant mediated neurodegeneration (7,10,11); particularly prone
to proliferation whilst supplies of Cu, Fe, Zn, Se within the
CNS are depleted - metals required as co factors in the major
radical scavenger enzyme/antioxidant groups; superoxide
dismutases 1/2 (SOD 1/2), glutathione peroxidase, catalases and
the antioxidant vitamin E (1)
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