Conference Report - Spongiform Encephalopathies Part 1

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MedGenMed Neurology

Conference Report - Spongiform Encephalopathies: A Tale of Cannibals, Cattle,

and Prions

Highlights From the 71st Annual Meeting of the American Society for Clinical

Laboratory Science; July 22-26, 2003; Philadelphia, Pennsylvania

Posted 09/17/2003

Sara M. Mariani, MD, PhD

Introduction

Prions -- are they viruses, nucleic acids, or " infectious " proteins?

 

This question has haunted the medical and research community for decades, and it

still puzzles investigators who are trying to discover the etiopathogenetic

mechanisms of a number of degenerative diseases usually defined as spongiform

encephalopathies. They are called transmissible spongiform encephalopathies

(TSEs) when there is evidence of animal-to-human or human-to-human transmission.

 

The definition stems from the characteristic aspect and consistency of diseased

tissues in the central nervous system (CNS), which appear at a close-range

examination to have acquired a spongiform appearance, owing to the accumulation

in neurons of an apparently inert substance called amyloid. In addition to the

accumulation of amyloid, human spongiform encephalopathies seem to share the

characteristic of long incubation times (from a few months to as long as 13

years) and, in many cases, a short illness.

 

Dr. Lynda Britton,[1] of the Louisiana Health Sciences Center, Shreveport,

presented an overview of the characteristics and causes of a number of

spongiform encephalopathies, in a symposium held during the 71st Annual Meeting

of the American Society of Clinical Laboratory Science in Philadelphia,

Pennsylvania. Many questions still surround the etiopathogenesis and clinical

course of these diseases -- but it is important to be aware also of the

existence and diagnostic features of the most infrequent ones, as the recent

cases of acquired Creutzfeldt-Jacob disease (variant, vCJD) have shown across a

whole continent.

 

North America seems to be have been spared, but surveillance has to be

exercised. In this regard, at the end of her presentation, Dr. Britton discussed

the formal recommendations of the Centers for Disease Control and Prevention for

blood transfusions, handling of surgical instruments, and the precaution

measures that may be adopted by international travelers. Further efforts need

also to be applied to achieve a better understanding of the chronic wasting

syndrome that has been recently described in North American cervids[2] (eg, deer

and elk) to ensure appropriate control of this disease.

 

 

 

 

Prions as Proteins

After many years of controversies (some of which are still raging), prions are

now believed to be the infectious agents responsible for the transmission of

TSEs.[3-9] They appear to be constituted by proteins that, in the absence of

detectable nucleic acids, acquire an abnormal configuration. They cannot be

destroyed by ultraviolet light, ionizing radiation, nucleases, or formalin, one

of the most common disinfectant/denaturing agents.

 

They usually present in an alpha-helix conformation with a ratio of alpha/beta

of approximately 42%, alpha to 30% beta (alpha-helix PrP-C); in pathologic

conditions, only 3% of the protein is folded as an alpha helix, while the vast

majority is present in an unfolded beta conformation (beta-helix PrP-Sc). The

molecular mechanism responsible for this unfolding process is not known;

chaperones (proteins that help other proteins to acquire their most stable

conformation) have been called into question, but no substantial evidence has

been found. Experiments aimed at reproducing prion infectivity in vitro have, so

far, yielded negative results. Following unfolding, beta-helix PrP-Sc is

believed to acquire a " malignant " behavior with propagation and ensuing neuronal

tissue damage.

 

The researcher who most actively proposed and supported the hypothesis that

prions were represented by proteins (protein-only hypothesis) was Stanley

Prusiner,[10-13] who in 1997 won a Nobel prize for his efforts. He first used

the word " prion " in a report published in 1992. Prions appear as highly

aggregated, detergent-insoluble structures that give rise to fibrillary

particles deposited in the brain, as documented by immunofluorescence

microscopy. Prions can be found mostly in CNS tissues, but they can also reach

high density in the cell membranes of white blood cells and platelets.

 

The fact that mice devoid of prion protein, following a gene knockout event, did

not develop prion diseases, and that mice carrying the PrP mutation observed in

affected humans spontaneously developed a TSE, has been taken as evidence that

prions are indeed necessary in this process.[14,15] Consistently, reintroduction

in the knockout mice of the prion protein appeared to make them susceptible to

the disease. The gene encoding PrP is located on chromosome 20, and its

conservation across a number of species leads some to believe that the normal

protein may have important physiologic functions. Mutations are mostly observed

at codon 129 with acquisition of a homozygous mutation to methionine.

No Nucleic Acid to Be Found?

The argument in favor of the existence or necessity of nucleic acid in these

structures has so far been defeated by experimental evidence. No trace of

nucleic acid has been found that might be held responsible for the " behavior " of

prions. Whether such nucleic acid does not indeed exist or whether it is too

small, hidden, or perhaps protected, is an open question that some have not yet

abandoned.

 

The alternative hypothesis, in fact, called the " virino theory " argues that

there are at least 15 different strains of prions. TSEs are seen as highly

heterogeneous diseases with highly heterogeneous incubation times (from 148 days

to 602 days in mice); they may consistently affect different parts of the brain

and result in different signs and symptoms. " How can all these differences be

explained by the simple unfolding of a protein? " argue the supporters of this

theory. Also, the characteristic patterns of interspecies transmission are taken

to suggest that the mechanism of " action " of prions is highly complex and can

hardly be ascribed to a simple protein-only structure.

 

Those who agree with the protein-only theory counter-argue that such differences

can still be explained by differences in folding abnormalities, and that

different conformations have been detected by Western blot analysis in prion

proteins. In addition, differences in glycosylation (lack of glycosylation vs

mono- or diglycosylation) may contribute additional levels of heterogeneity.

 

 

Contunued in Part 2

 

 

 

 

 

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