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doi: 10.1097/01.NT.0000430854.67226.f0
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BOOKSHELF: A Lively Tale of Proteins Gone Awry: Fatal Flaws: How a Misfolded Protein Baffled Scientists and Changed the Way We Look at the Brain.By Jay Ingram. 296 Pages. Yale University Press 2013.

Filley, Christopher M. MD

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One of the most intriguing ideas to emerge from neuroscience research in recent decades is the proposal that an infectious disease can be caused by a protein. At first glance, such an idea seems preposterous, seemingly violating all that is known about infectious organisms and even challenging basic assumptions about life itself. How can a mere protein, no more than a string of amino acids, produce a devastating brain infection? And more generally, does this phenomenon necessitate a re-definition of life itself, which has heretofore been regarded as requiring the agency of nucleic acids?

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These questions lie at the core of Jay Ingram's informative and entertaining book — Fatal Flaws: How a Misfolded Protein Baffled Scientists and Changed the Way We Look at the Brain. The book leads the reader on a journey from the early observations of neuroscientists in the eastern highlands of New Guinea to provocative laboratory findings on what came to be widely known as the proteinaceous infectious particle or prion.

The story of kuru and its investigation in the 1950s, familiar to many both within and outside the neurosciences, begins this account. While the discovery that cannibalism transmitted this dreadful disease inevitably invokes a lurid fascination all its own, Ingram engagingly describes the work of Carleton Gajdusek, whose prodigious intellect and energy led to this conclusion and later to a Nobel Prize. At that time kuru was regarded as one of the putative “slow virus” infections of the brain that had a long incubation period before culminating in an invariably fatal outcome. This paradigm dominated research on these mysterious diseases into the 1970s; the rapidly progressive dementia of Creutzfeldt-Jakob disease (CJD) was commonly thought to result from a slow virus infection.

At this point the imposing figure of Stanley Prusiner enters the scene. In a major paper in Science published in 1982 entitled “Novel Proteinaceous Infectious Particles Cause Scrapie,” Prusiner boldly proclaimed the existence of prions as the infectious agents causing not just scrapie, a disease of sheep and goats, but kuru and CJD as well. This article proposed a radical shift in the understanding of infectious disease, summarizing evidence for the transmissibility of disease by proteins alone.

Not surprisingly, the idea immediately generated much controversy and strong reaction from skeptics, including many who found it difficult to accept that the devastating clinical features of CJD could result from a mere protein gone astray in the brain. Undaunted, Prusiner held firm, tirelessly working to confirm his proposal, and much of the book is devoted to his perseverance in promoting his views on protein misfolding in the face of often very visible opposition. Ingram candidly recounts the details of this academic conflict, pointing out that Prusiner's vigor in the debate has been seen as evidence for both steadfast commitment to a brilliant line of inquiry or, alternatively, headline-grabbing self-promotion. But as the years have passed and more work has been done, the concept of prions has clearly gained increasingly widespread acceptance, despite the objections of neuroscientists, such as Laura Manuelidis, who continue to maintain that CJD and related diseases are caused by slow viruses after all.

CJD and its relatives are rare diseases, however, and for a time the dispute over prions mainly preoccupied the halls of academe. The situation changed dramatically in the 1990s, when growing numbers of young adults in England were recognized as having a rapidly progressive dementia with often florid psychiatric features that was determined to be acquired from eating infected beef. This disease was named variant CJD, and traced to an affliction of cattle identified in the 1980s known as bovine spongiform encephalopathy (BSE) or “mad cow disease.”

Variant CJD generated enormous alarm about a potential epidemic related to the consumption of readily available beef, and major public health efforts followed as millions of British cows were slaughtered to prevent the spread of disease. Whereas variant CJD was effectively addressed and seems controlled for now, anxiety persists because the long incubation period of the disease implies that some cases may yet appear, and people who are infected may unwittingly transmit the disease by blood transfusion even while asymptomatic. These concerns are troubling whether or not the infectious agent is a prion.

The tale next moves across the Atlantic to the United States, where the problem of chronic wasting disease (CWD) among deer and elk has led to considerable uneasiness. First identified in 1967 among captive mule deer in northern Colorado, CWD is thought to be transmitted among cervids via prions, and cross-species transmission to humans is considered at least plausible.

If people can develop variant CJD after eating beef with BSE, why not a similar transmission of dementing illness to people consuming game with CWD? Given that CWD is now found in many parts of North America including Canada, and that many thousands of people ingest wild deer and elk, the potential for humans contracting this disease cannot be dismissed. Fortunately no human cases of CWD have been identified, although surveillance for such a disease is complicated by the fact that no one knows how a human infected with CWD would actually present clinically.

Ingram then turns to Alzheimer's disease (AD) and Parkinson's disease (AD) as other avenues to explore the saga of prion neurobiology. Similar to CJD, both of these diseases feature prominent protein misfolding — amyloid-beta and tau in AD and alpha-synuclein in PD — and perhaps both should be recast as prion diseases. Prusiner postulated as much in his 1982 paper, suggesting that these and several other idiopathic disorders might all be explained by such a proteinopathy. However, at least for now, it is widely thought that neither AD nor PD are infectious, and the sweeping speculations of Prusiner thirty years ago remain conjectural.

A final disorder considered in the context of prions is the recently described entity of chronic traumatic encephalopathy or CTE. In this highly publicized but still poorly understood condition, the protein at issue is again tau, as some professional athletes with repeated concussions during their playing days have developed progressive dementia with prominent tauopathy discovered at autopsy. Is this a prion-like process? Far too little is known to permit even a preliminary answer, but CTE is another disorder in which protein misfolding may play a role at some point in the pathogenetic cascade.

Fatal Flaws is a wide-ranging and readable book that sets forth the main elements of the remarkable proposal that proteins by themselves can be agents of human disease. The concept of the prion is highly relevant to neurology, and generates a host of questions on the fundamental nature of infectious diseases, the pathogenesis of neurodegeneration, and the very definition of life.

Many readers familiar with this work will likely find far-fetched the notion that prions are responsible for diseases such as AD, PD, and CTE, but few will dispute that they are indeed implicated in CJD and other similar diseases that used to be called slow virus infections. The work of Carleton Gajdusek and other early investigators in this field stands out in this volume, and, in particular, the contributions of Stan Prusiner, who won his own Nobel Prize in 1987, come across as transformative. How much the idea of the prion will illuminate broader areas of neurobiology remains to be seen, but this book makes clear the profound change in thinking that has already occurred.

Dr. Filley is professor of neurology and psychiatry and director of the Behavioral Neurology Section at the University of Colorado-Denver School of Medicine.

©2013 American Academy of Neurology

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