Are cheetahs on the run from prion-like amyloidosis?

The misfolding and aggregation of proteins is often an accident waiting to happen. Consequently, organisms have developed sophisticated chaperone and quality-control systems to limit abnormal protein interactions and the accumulation of toxic aggregates (1). However, sometimes these systems can be overwhelmed, and diseases, namely protein misfolding diseases, can result. One such disease, amyloid protein A (AA) amyloidosis, is wreaking havoc in the captive cheetah population, complicating efforts to rescue this endangered species from extinction (2, 3). One key to managing this fatal disease in cheetahs is to understand why it is so prevalent. Most cases of AA amyloidosis in mammals appear to occur spontaneously, usually as a result of chronic inflammation or genetic peculiarities that predispose the organism to the deposition of serum amyloid A (SAA) protein in fibrillar deposits called amyloid (Fig. 1). In this issue of PNAS, Zhang et al. (4) report that AA amyloid is excreted in the feces of cheetahs with AA amyloidosis and that this fecal amyloid can in turn promote a similar disease in mice. These results suggest that cheetah AA amyloidosis may not be simply a spontaneous disease, but also a natural prion-like, transmissible protein misfolding disease. Diagram of AA amyloid formation and the potential prion-like transmission of AA amyloidosis by fecal shedding and oral uptake of the amyloid. The photo shows an example of Congo red-stained AA amyloid fibril deposits in hamster liver tissue (courtesy of John Coe, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases). Prions are protein-based infectious agents or elements of inheritance that, unlike conventional pathogens, lack agent-specific nucleic acid genomes (5, 6). Prions have been described in both mammals (e.g., bovine spongiform encephalopathy and Creutzfeldt–Jakob disease) and fungi …