some believed was associated with cannibalism [1, 2]. Kuru was first discovered in the Fore tribe, with victims trembling, losing muscle control, laughing uncontrollably, and dying within months. The disease primarily affected women, with a female-male ratio of 14:1 in adults. In 1959, William Hadlow, an American veterinarian working on scrapie, happened to visit an exhibition on kuru in a medical museum in London [3]. He was shocked to find striking similarities between the two progressive degenerative diseases, from the signature “soap-bubbles” in the nerve cells, the extensive incubation period, to the failure in isolating a microbial agent [4]. After that, Hadlow wrote a letter to the editor of The Lancet, and also reached out to Gajdusek, drawing scientists’ attention to the high resemblance of the two diseases [5]. Later, Igor Klatzo, a neuropathologist who studied the brains of 12 kuru patients received from Gajdusek, also drew parallels between kuru and another human spongiform brain disease, Creutzfeldt-Jakob disease (CJD) [6]. In the next decade, scientists were able to experimentally transmit kuru and CJD to chimpanzee by inoculating infected human brain tissue, and later to laboratory rodents [1]. For kuru, we now understand that the disease spread through cannibalism: Female relatives would consume their relatives’ bodies as a mortuary practice “to free the spirit of the dead [7, 8],” during which they ingested the infected human brain concentrated with the infectious agent. Creutzfeldt-Jakob Disease: Lessons to Scientists So, what was the infectious agent? Stanley Prusiner, an American neurologist and biochemist, recalled the bizarre observation in his CJD patients: There was no immune response elicited – no fever, no increase in white blood cell count, and no humoral immune response – meaning that whatever caused the disease might not be a foreign agent [9]. With his biochemistry background, Prusiner decided to approach the problem differently by attempting to purify the infectious agent from affected mice inoculated with scrapie agent [9]. After harvesting and blending the spleens and brains of the mice, the homogenate was centrifuged for different times and speeds to separate constituents with different densities. After testing the infectivity of each sample, a highly infectious fraction was recovered despite the removal of over 98% of proteins and polynucleotides. With this cleaner sample, scientists demonstrated that infectivity could be reduced by procedures that hydrolyze or modify proteins, eventually leading to the discovery that the culprit wasn’t a microbe at all, but a misfolded protein. Prion: The Misfolded Protein Proteins are essentially amino acid chains, which are folded into precise shapes to function properly. Despite the lack of knowledge about its precise function, prion (PRNP) gene encodes normal prion protein which is active in the brain [10]. However, the amino acid chain somehow misfolds, and these deformed proteins, usually referred to as “prions”
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