Microbiology and Immunology

BSE, scrapie, and CJD: recent advances in research WORLD OF MICROBIOLOGY AND IMMUNOLOGY

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familial disease (determined by genetic testing, by identifying

two or more first-degree relatives with CJD or, if there is no

information, by a precautionary assumption of familial dis-

ease); recipients of products derived from human pituitary

glands; and recipients of corneal or dura-mater grafts.

The risk of transmission of CJD through blood, blood

products, and organ or tissue transplants, is being addressed

by, for example, the Laboratory Centre for Disease Control

(LCDC) in Canada. They are planning to initiate an enhanced

surveillance system for CJD throughout Canada. Cases will be

reported to the surveillance system by specialists in neurology,

neuropathology and geriatrics. Through record review, inter-

view, genetic sequencing and neuropathological examination,

extensive information about every person suspected of having

CJD will be collected and compared with data from a control

population to ascertain the relative risk of CJD associated with

exposure to blood and blood products. In addition, Canada has

been invited to participate in European Concerted Action on

CJD, an international surveillance program for variant CJD

coordinated by investigators in Edinburgh. This obviously has

ethical implications for patient privacy and it is questionable if

such extreme measures are really necessary. The prion agent is

not new unlike HIVand other emerging agents and there is an

absence of any recorded cases of CJD among people with

hemophilia and recipients of multiple transfusions or people

who abuse injection drugs. Also, a small case-controlled study

in Britain revealed no risk for the subsequent development of

CJD associated with receiving blood.

See alsoBSE and CJD: recent advances in research; Public

health, current issues

BSE, SCRAPIE, ANDCJD: RECENT

ADVANCES IN RESEARCHBSE, scrapie, and CJD: recent advances in research

Bovine spongiform encephalopathy (BSE) in cows, scrapie in

sheep, and Creutzfeldt-Jakob disease (CJD) in humans are

examples of prion diseases. The central event in the pathogen-

esis of these fatal disorders is hypothesized to be the post-

translational conversion of a normal host protein of unknown

function, termed PrPC into an abnormal isoform called PrPSc.

The idea that protein alone can carry information sufficient to

ensure its own propagation was an unprecedented challenge to

the “central dogma” of molecular biologywhich essentially

states that nucleic acids, not proteins, are the biological infor-

mation carriers. The work that led to current understanding of

prion diseases originated more than four decades ago. In the

1960s, Tikvah Alper and her co-workers reported that the

scrapie agent was extremely resistant to treatments that nor-

mally destroy nucleic acids, but sensitive to procedures that

damage proteins. Furthermore, the minimum molecular size

needed in maintaining infectivity was too small to be a virus

or other known infectious agent. These results led J. Griffith to

propose that the material responsible for transmitting scrapie

could be a protein that has the unusual ability to replicate itself

in the body. Extensive work by Stanley Prusinerfinally led to

the purification of the PrP protein. For the next two decades,

most research on prion diseases has focussed on the abnormal

PrPSc and consequently, the functional role of PrPC has

remained an enigma. Recent advances in the field of prion

research, however, suggest that PrPC is a copper binding pro-

tein and has a modulating role in brain oxidative homeostasis.

On the basis of in vitrostudies by D. R. Brown at the

University of Cambridge, it would appear that PrPC may act

as an antioxidant enzyme in a similar manner to superoxide

dismutase. The presence of the copper ion is essential for such

a function.

Much recent evidence suggests that alterations in metal-

lochemical processes could be a contributing factor for the

pathological process in neurodegenerative disorders, includ-

ing Alzheimer’s disease and now possibly prion diseases. The

PrPC protein has recently been found to have a region at its N-

terminus, which is able to bind copper tightly and other met-

als, such as nickel, zinc and manganese, less tightly. One of

the biochemical differences between the PrPC and PrPSc that

was recognized very early is the surprising resistance of PrPSc

to proteases (enzymesable to degrade proteins). In vitrostud-

ies have shown that if manganese ions replace the copper ions

in the PrPC protein, it undergoes a structural change and

becomes protease resistant. Furthermore, the binding of man-

ganese to PrP dramatically reduces its superoxide-dismutase

activity, suggesting that its cellular function may be affected

under these conditions. Whether these in vitro changes

brought about by different metal ions resemble the changes in

PrP during prion disease is still to be confirmed, but the results

are certainly suggestive. Research in this direction is pro-

gressing in several institutions in the UK at the moment.

High concentrations of metals are found in the brain and

to prevent neuronal damage triggered by these elevated con-

centrations, the brain has evolved efficient mechanisms to reg-

ulate the availability of these metals. Metals are required for

the normal functioning of the brain, such as the proper trans-

mission of synaptic signals, which involve the release of zinc,

copper and iron by neurons. At the same time, metals are an

integral part of the cellular defense system, as they are often

bound to antioxidant proteins and protect the brain from dam-

age by free radicals. Although metals are essential to the nor-

mal functioning of the brain, perturbation in metal levels can

upset cellular protein behaviour and possibly lead to neuro-

logical disorders. In Alzheimer’s disease, for example, the lev-

els of copper, zinc, and iron were found to alter in severely

degenerated brain regions. In the hippocampus and amygdala

regions, the levels of both zinc and iron were increased while

the levels of copper were decreased.

In the 1970s, Pattison and Jebbett showed that when

mice were fed with cuprizone, a copper chelator, it induced

histopathological changes reminiscent of scrapie in sheep and

further analysis indicated similar biochemical changes. Also a

recent report by Mark Purdey showed that in the ecosystem

supporting isolated clusters of sporadic prion diseases in

Colorado, Iceland, and Slovakia, a consistent elevation of

manganese concentration in relation to normal levels recorded

in adjoining prion disease-free localities were detected.

Evidence has also emerged concerning the metal content of

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