Advances in Spongiform Encephalopathy

Well into the 1970s, members of the Fore tribe of Papua New Guinea were afflicted by a devastating neuro-degenerative epidemic known as kuru. The disease shares considerable similarity with spongiform encephalopathy first described by the German physician/scientists Hans Gerhard Creutzfeldt and Alfons Maria Jakob in the 1920s, CJD for short. Often more than a decade after infection, the afflicted develop conspicuous trembling and severe motor dysfunction as a consequence of progressive nerve cell death in the central nervous system. The video below portrays the symptoms of this horrible disease graphically. Some readers may find the footage disconcerting.

As a consequence of nerve cell degeneration, the brain tissue shrinks in places. Microscopic holes pockmark the tissue like a sponge in histological preparations.

Kuru may have been acquired through the inheritance of defective genes. Isolated tight-knit island communities like the tribes of Papua New Guinea are known to be particularly vulnerable to inheritable genetic defects because of their limited gene pools. Indeed, genetic mutations seem to cause spongiform encephalopathy. Recently, Wang and others (2008) provided evidence for the underlying molecular mechanisms.

Peculiarly, among the Fore of Papua New Guinea particularly women and children developed kuru. The Fore were known to ingest the bodies of deceased loved ones during funeral rites in order to capture their life forces. Women and children ate mainly brain parts. Perhaps the origin of the disease was passed along with the brain tissue. In support of this idea, the late American Nobel Prize-laureate Daniel Carleton Gajdusek proved that kuru was indeed an infectious disease that could be transmitted even to other primates. Curtailing cannibalism on the islands would drastically reduce the occurrence of the disease.

Years later, Stanley Prusiner would win the Nobel Prize for ultimately identifying the molecular basis of the transmitted variant of spongiform encephalopathy. The infectious agent was not an organism. Nerve cells incorporated misfolded proteins known as prions that attached to native forms of functional cellular proteins, forcing them to undergo a similar conformational change. Like a snowball, the dysfunctional protein grows forming amyloid plaques that eventually destroy the cells.

Misfolded prions are fairly stable, temperature resistant molecules, remaining active even in soil outdoors for decades. Scrapies, which causes spongiform encephalopathy among sheep and goats, is believed to be contracted through fodder contaminated with urine and feces from infected animals.  Bovine spongiform encephalopathy (BSE), popularly known as Mad Cow Disease, has been shown to be transmitted by protein-enriched power feed contaminated with prions. Beef from infected cattle may cause CJD in people.

Remarkably, however, some highly-exposed Fore remained unaffected by kuru. In this week's issue of the New England Journal of Medicine, researchers at University College of London report that they found a new variant of the gene PRNP encoding prion protein that is unique to the resilient tribal members and may improve resistance to the disease (Mead and others, 2009). The newly discovered genetic variant, called G127V, appears to render the native prion protein less pliable to conformational change induced by misfolded protein. It was detected in half of the women who were homozygotes for an already known resilience factor. That is, they possessed identical variants of PRNP on both chromosomes carrying the gene. By contrast, tribespeople who succombed to kuru did not possess this variant, and it is absent from the global human population unexposed to the disease.

This discovery does not only open new avenues for the treatment of spongiform encephalopathy, but moreover further affirms genotypal variation and phenotypal selection as fundamental evolutionary forces that affect all living things as Charles Darwin proposed in his theory published in "On the Origin of Species" almost to the day 150 years ago. Darwin would have been delighted to learn about this finding, particularly in the year of his 200^th birthday.

References

• Mead S, Whitfield J, Poulter M, Shah P, Uphill J, Campbell T, Al-Dujaily H, Hummerich H, Beck J, Mein CA, Verzilli C, Whittaker J, Alpers MP, Collinge J (2009) A Novel Protective Prion Protein Variant that Colocalizes with Kuru Exposure. New Eng J Med 361:2056-2065.
• Wang XF, Dong CF, Zhang J (2008) Human tau protein forms complex with PrP and some GSS- and fCJD-related PrP mutants possess stronger binding activities with tau in vitro. Mol Cell Biochem 310: 49–55.

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