|
Trail:
Ultra Violet
page 2
page 3
page 4
page 5
page 6
page 7
page 8
|
 Scientific
papers - Ultra Violet - page 4
DOES PrPc PLAY A FUNCTIONAL ROLE IN NEUTRALIZING THE RADICALS GENERATED
BY A RANGE OF ENVIRONMENTAL OXIDANTS?
PrP expression has been consistently upregulated in vitro, in response
to oxidative challenge of PrP neuroblastoma cells (45).Loss of PrP's
Cu-mediated antioxidant SOD function (6) following an Mn substitution at
PrP's Cu vacated domain (5), coupled to a low external availability of
antioxidant cofactor minerals Se/Cu/Zn in the environment (4) could
impair the overall antioxidant capacity of the CNS to neutralize
incoming challenge by environmental oxidants.
PrP mRNA is intensively expressed in various neuroectoden-nal cell
lines, such as retinoblastoma/melanoma, and in epithelial cell lines
(77). Such a distribution suggests that PrP could putatively serve as a
critical 'back-up' link in the porphyrin/melanin chromophore chain as a
type of 'photooxidative shock absorber' *
Ultra violet radiation is widely recognized as producing superoxide
radicals in the contexts of UV-induced degradation of tryptophan (7 p.
291), following UV absorption by some porphyrin and exogeno-us chemical
photosensitizers (dyes, etc.) (7) p. 62) and when LTV is absorbed by the
pheomelanin type of melanin chromaphore (7, p. 141/62) which fails to
self-neutralize the superoxides generated by their own UV absorption
(14). PrP's Cu-mediated antioxidant activity could serve to neutralize
these superoxides, as well as singlet 02 and other interchangeable
radicals resulting from the impact of incoming oxidants.
However, the distribution of PrP mRNA expression is not exclusively
confined to the aforementioned types of ectodermal cell. PrP mRNA can
also be expressed - at albeit less intensive concentrations - in lung
alveolar, some gastrointestinal membranes, the tonsils, appendix, the
olfactory/nasal tract, etc. (77,2), which may imply that our mammalian
biological systems have harnessed PrP's antioxidant capacities to
scavenge a wide array of incoming oxidative assaults delivered by
several types of environmental oxidizing agent (e.g. UV, ozone, metals,
pesticides, microwaves (mobile phones, radio transponder collar in
bovines) etc.) (7) via several exposure routes (e.g. ocular, skin, lung,
gastrointestine tract, nasal--olfactory, etc.). Exposures to ozone,
heavy metals, pesticides and microwaves are all recognized to generate
superoxide and other radicals in biological systems (7,8, p. 396).
The specific route of exposure and the specific oxidative potency of the
environmental oxidant involved, coupled to the specific PrP genotype of
the exposed individual, could dictate which 'strain' of TSE will emerge.
EVIDENCE SUGGESTS A METABOLIC INTERRELATIONSHIP EXISTS BETWEEN MN, UV
CHROMOPHORES AND PrPc IN THE PHOTOBIOLOGICAL RESPONSE
Mn/PrPc association with UV chromophores
Interestingly, Mn is one of the key metals that are integrated into the
molecular structures of UV-absorbing chromophores in both mammals and
plants (10,13,11, 12,78,79), hence the industrial use of Mn in
luminescent materials. Mn melanins are involved in UV absorption in
mammals, where the free radicals that are integral to the structure and
function of melanin (14) are employed as electron acceptors in the
process that neutralizes radicals generated by UV-mediated
photooxidation - the negative side-effects of the healthy
photobiological response.
The most intensive concentrations of Mn in the mammal appear in the
mitochondria-rich melanocyte cells of the retina, the pineal, the skin
and pituitary (11,12) - key regions where Mn chromophores are expressed
for absorbing UV photon energy and/or its resulting 'excitation energy'
that is relayed in the form of fluorescence emission to further
acceptor/donator molecules down the line (8,7); ultimately transferring
that energy to influence turn over of the central melatonin-serotonergic-
endocrine pathways which preside over the circadian regulation of
certain reproductive, sleep/wake, behavioural functions etc. (80).
Intriguingly, PrP mRNA is expressed in these same locations - retino
melanoma epithelial, etc. (77) suggesting that a shared functional role
may exist between PrP and Mn chromophores; where each constitutes a
contiguous link in the metabolic chain that neutralizes singlet oxygen
and superoxide types of radical generated by the aforementionined
contexts of UV absorption.
PrP and Mn coexist within many specialized cells and mitochondria-rich
zones throughout the CNS; such as the hippocampal gyrus, cerebellum,
reticular formation, neocortex, astrocyte cells (9,48,85,1,2) - areas
which are all implicated in the daylight-darkness circadian
melatonin-serotonergic-endocrine pathways (80).
Blind/pinealectomized sparrows and neonatal rats have still maintained
normal endocrine response to the external light cycle (86), suggesting
the presence of a hitherto unknown capability for extra-ocular/pineal
photoreception in mammalian organisms. If light is exclusively
introduced directly to the hypothalamus of female rats via quartz rods,
the oestrous cycle has still been significantly influenced (87). Light
has also been shown to penetrate deep into the brain of mammals that
have skulls as thick as sheep (88)!
The co-presence of Mn and PrP in the mitochondria rich CNS astrocytes
(9,85), etc. suggests a shared metabolic function or interaction between
the two. In this respect, Brown et al. have found that PrP expression
influences Mn uptake (5) into cells.
THE PrPc-CHROMOPHORE BOND: DOES Cu-PrPc QUENCH SINGLET 0 / LUMINESENCE
GENERATED BY UV EXCITED CHROMOPHORES/XENO-PNOTSENSITISERS?
The additional complicating factor of significant levels of various
systemic xeno-photosensitising chemicals that have been consistently
observed in TSE ecosystems raises the distinct possibility that the Cu
histidine domain of PrPc may perform a specific protective role in
bonding to these exogenous photosensitiser pollutants (Fig. 4). For
PrPc's Cu domain is known to bond 'in vitro' to the photosensitisers;
congo red dye, porphyrins, etc. (81-83), thereby scavenging/quenching
the singlet oxygenllight energy that is generated when these molecules
are exposed to UV radiation or internal light emissions. This
possibility is supported by many trials that have demonstrated the role
of Cu as a quencher of singlet O luminnescence - one such study
demonstrates how CU2+ inhibited the production of singlet oxygen and
chemiluminescence after it had been conjugated onto a photoenergised
formamidine photosensitiser pesticide molecule called Amitraz (84).
In this respect, the capacity for 'in vivo' expression of PrPc on the
surface of phagocytes (neutrophils, etc.), in microglial cells, the gut
wall and lipid membranes (2), may simply indicate an extension of the
photo-excito absorbing function of PrPc, where Cu-PrPc is employed to
scavenge/quench singlet oxygen and the resulting light emissions
(luminescence) that are generated in these various contexts, e.g. by
activated phagocytes, the respiratory burst of microglial cells,
worm/fungal infestations in the gut and following lipid peroxidation of
membranes respectively (7, p387).
The possibility of a metabolic interrelationship existing between PrP
and porphyrin/phthalocyanines can be speculated following trials which
demonstrated how several types of porphyrin bond to PrP histidine sites
and block the conversion of normal PrPc into abnormal PrPsc (83).
The intense concentration of tyrosine in PrP's amino acid sequence (77)
may indicate that PrP performs a dual melanin-like role in the
photobiological response; e.g. by serving as both a scavenger of the
radicals generated by photooxidative stress and - by virtue of PrPs
tyrosine amino acids - as a chromophore which quenchs the energy of
fluoresence emitted by a prior-in-line donor molecule such as melanin or
a xeno-photosensitiser. As the degree of efficiency of fluorescence
transfer is totally dependent upon the conformational status of the
chromophore molecule involved (89), the putative role that PrP performs
as a 'photooxidative shock absorber' may collapse once Mn has
substituted at the vacated Cu domain on PrPc causing formation of the
misfolded protease-resistant PrP isoform.
Furthermore, the low copper status of the CNS resulting in mammals
dependent upon low-Cu ecosystems (85) Cow Cu recorded in TSE ecosystems
(4)) would cause a considerably reduced turnover of melanin synthesis
due to the sole dependence of melanin's catalytic pathway on the
Cu-mediated oxygenase enzyme, tyrosinase (89). The same scenario would
apply to the turnover of the Zn dependent chromophore, phthalocyanine
(89), whose turnover would decrease in mammals thriving off Zn deficient
ecosystems (4).
The low-Cu/-Zn that is characteristic of TSE ecosystems (4) would
therefore predispose mammals thriving off such foodchains to an
inadequate synthesis of protective chromophores, thereby rendering such
individuals highly vulnerable to both the deleterious impact of
photooxidative stress and to the loss of the protective effect that
these chromophores exert in inhibiting the conversion of PrPc into its
rogue prion form (83).
|
