Transmissible spongiform encephalopathy in the 21st century

There is no shortage of recent reviews on various aspects of transmissible spongiform encephalopathy (TSE),^1–12 but none has been addressed to clinical neurologists in the hope of providing a reasonably brief and non-technical summary of the more important advances since the turn of the century. The beneficiary of opinions from members of both the basic and clinical research communities, this synopsis was undertaken to strike a readable compromise between the depths of specialized reviews and the shallows of abstracts generated by Internet search engines (PubMed lists 934 entries for Creutzfeldt-Jakob disease [CJD], 2,170 entries for TSE, and 4,729 entries for prion disease published since the turn of the century).

THE PATHOGEN

After more than 60 years of study, the most basic questions concerning the infectious agent—exactly what it is, and how it replicates—have not been fully answered. Because of 1) the consistent failure to find any disease-specific foreign nucleic acid or protein and 2) the almost equally consistent finding of a host-encoded but misfolded prion protein (PrP^TSE) in the brains of affected humans and animals, a consensus has arisen (but still not formally proven) that favors the protein as the principal if not sole cause of disease. Over 30 different mutations in its encoding gene (PRNP) on chromosome 20 are responsible for the different forms of familial CJD, and one important polymorphism at codon 129 (encoding methionine or valine) influences susceptibility and clinical characteristics in all forms of human disease. The first convincing evidence for a physiologic role of the normal protein (PrP^C) is the recent surprising finding that it regulates β-secretase cleavage of the Alzheimer amyloid precursor protein.¹³

The proposed sequence of events in TSE is that the normal protein, which is a soluble proteinase-sensitive and α-helix-rich glycoprotein of approximately 35 kD molecular weight, misfolds via one …