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Other
foreign transition metal cations which can bond to Cu histidine ligands
(35)(36)(37) should not be discounted as further alternative candidates
for replacing Cu on PrPc, thereby priming the prion for suceptibility to
TSE. Environmental studies of TSE clusters by the author have
identified the significant presence of silver (Ag) and bismuth (Bi)
pollutants.
See Table1 and Table
2
In some TSE cluster regions, where Ag
had polluted these environments following its use (38) in weather
modification cloud seeding, water purification, mining, photographic
developing, and in the context of risk factors for CJD, the use of
Ag (36) in dental amalgam fillings, surgical instruments/plates,
intranasal inhalant antibacterial sprays, etc. Ag and Bi
can also compete for binding to histidine ligands (35)(36)(37) on
proteins, whilst Ag in particular will compete for Cu ligands in
preference for any other competing metal.
Contamination
of the Cu depleted brain by a particular replacement cation would
present its own specific strain-type of TSE (4), whose clinical and
neuropathological profile reflects the specific conduction/magnetic
status of the foreign metal substitute involved. Ag and Bi can also be
oxidized, like Mn, into trivalent species rendering them susceptible to
phonon/photon absorption, etc (39).
Whilst
Mn is paramagnetic, Ag and Bi are both diamagnetic (33). Ag or Bi
strains of TSE can be envisioned where the diamagnetic silver/bismuth
prions instigate an abnormal state of ‘superconduction’ of
electromagnetic energy through the circadian pathways- instead of the
steady state of conduction provided by Cu prions.
It is
interesting that reversible CJD-like encephalopathies have been
regularly recorded in humans who have been prescribed Bi-based
pharmaceuticals and cosmetics (40). These cases remitted following
cessation of treatment, although it could be speculated that the
syndrome may have advanced to a fully fledged, irreversible CJD had the
Bi treated individuals simultaneously lacked an available supply of Cu
in their CNS; thereby enabling a Bi substitution at PrP’s vacant Cu
domain to proceed.
Supporting
evidence for the environmental TSE origin theory
Once
these external environmental factors bring about a depleted Cu/Zn and
superfluous Mn status in the mammalian brain, then PrPc’s Cu domain
becomes vulnerable to bonding with Mn in place of Cu. The original
published hypothesis that proposed “a foreign Mn cation
substitution at the vacant Cu domain on the PrPc” (4) was put to
challenge in a cell culture experiment conducted by Dr David Brown at
Cambridge University (41). The results confirmed this hypothesis,
whereby Mn loaded/Cu depleted prion protein cells yielded the protease
resistant PrP isoform which characterises the TSE diseased brain. This
was the first time that protease resistant PrP had been experiment
generated via a de novo transformation.
Alan
Prescott et al’s research at Dundee University (42) has shown that Mn
can cause protein misfolding by disrupting membrane dynamics along the
secretory pathway. The authors suggest a delicate regulatory mechanism
operates to enable healthy protein secretion which is maintained via a
delicate balance of golgi associated Cu transporter proteins and Mn
transporter proteins
Further
research by Boon Seng Wong at Case Western University’s National US
Prion Surveillance Unit in Cleveland, USA (43), revealed a ten fold
increase of Mn and 50% reduction of Cu in the brains of those who had
died of sporadic CJD in relation to controls. The Prions were largely
bonded to Mn rather than Cu in these various CNS sections.
Research
by Roumiana Tsenkova at Kofu University (44) investigated the hydration
and binding properties of PrP using near infrared spectroscopy. This
work concluded that the Cu bonded PrP formed a stable, ordered hydration
of the protein - enabling correct folding processes - whereas Mn bonded
PrP demonstrated totally different spectral characteristics.
Research
at Leeds University using murine PrP (45) has demonstrated that PrPc is
rapidly endocytosed following exposure to Cu and Zn, but fails to
endocytose in the presence of Mn. This work shows that a cessation of
the healthy endocytosis of PrP occurs in Mn treated cells; probably
instigated by some Mn mediated disruption at the octarepeat region of
PrP – presumably via Mn binding.
Therapy
with chlorpromazine has been shown to be beneficial to victims of vCJD.
Interestingly, Cotzias demonstrated that chlorpromazine exerts its
therapeutic benefits by specifically targeting and combining with Mn 3+,
as well as competing for protein ligands with Mn 3+ (46).
Overview
of the working TSE origin hypothesis
It is
difficult to attribute the full spectrum of clinical and pathological
abnormalities encountered in TSEs to the sole pathogenic activities of
the prooxidant prion agent. Indeed, Lasmeras et al (47) transmitted TSE
into laboratory animals via intracerebral inoculation of TSE affected
CNS homogenate, and the resulting TSE diseased CNS tissues of those
recipient animals failed to demonstrate the presence of ‘prions’ at
post mortem.
The
hypothetical case for the manganese 3+ component as the pathogenic agent
addresses these ‘missing links’ well, since the progressive delayed
neuropsychiatric syndrome encountered by Mn miners and other cases of Mn
intoxication (35)(48)(49)(50)(51)(52) displays a clinical and
neuropathological profile which virtually duplicates the profiles seen
in TSE. Shrunken and distorted basal ganglia (putamen and caudate nucleii)(53), astrogliosis, amyloid plaques,
neuronal loss, degenerating serotonergic/dopaminergic neurones, amyloid fibrils (50), etc, are key neuropathological features observed
in both Mn neurotoxicity and TSEs (16).
The
simple fact that Cu is employed in electric cabling as a conductor
whilst Mn is employed in batteries for absorbing and storing up electric
energy
may
elucidate the underlying cause of TSEs; where healthy Cu prions conduct
the vital electro energy (derived from the sun’s ultra violet and
earth’s geomagnetic, infrasonic waves) along the circadian
pathways, whilst the aberrant metamorphosed Mn 3+ prions serve to
blockade and permanently store up those incoming magnetic energies to
levels which exceed the explosive ‘flash point’- thereafter
detonating neuropathogenic cluster bombs of free radical chain
reactions along the circadian pathways.
This
new concept of the “ferrimagnetised metal’ as the pathogenic
co-partner component of the prion could explain why the so called
infectious property of prions cannot be destroyed until extremely
high temperatures are reached (1)(4). In this respect, once the
‘infectious agent’ is exposed to sufficiently high temperatures that
exceed the “curie point” for that cation (eg 550 degrees), the
thermal agitation of atoms is sufficient to depolarise the permanently
magnetised status of the metal. Once the metal has cooled below the
curie point again, any subsequent re-exposure to external magnetic
fields would be sufficient to re-prime the pathogenicity of the
remaining prion fragment.
With
an overabundance of Mn prions and loss of Cu prions, the oxidative
impact of the various electromagnetic energies received at the Cu
deficient retina or cochlear hair cells, etc, can no longer be quenched. Consequently the photon/phonon energy flow of incoming UV,
infrasound, etc, piles up, being absorbed by the piezoelectric Mn atoms;
only to find the mounting oxidative capacity misappropriated into
converting the innocuous Mn 2+ prions into potentially lethal, prooxidant Mn 3+ or 4+ prion species. In this respect, any accumulation
of protease resistant Mn 3+ PrP in the CNS finds itself vulnerable to an
acoustic shock induced metamorphosis that may strike at a later date.
The
Mn contaminated/Cu depleted brain is unable to deal with the incoming
flow of various forms of EMR from the external environment –
particularly once levels of radiation reach high intensities. The
incoming energy is hijacked and perverted into unleashing a ‘Jekyll
and Hyde’ like property of PrP; where the protein transmutates from
innocuous ‘sleeping’ to fully fledged ‘pathogenic’ form; which,
in turn, kicks off a whole chain reaction of free radical mediated
assault on brain cells. A self perpetuating melt down of
neurodegeneration bursts forth, and TSE ensues.
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