The detection of corrupt prions (1)

PHOTO: www.wrp-n.org

PHOTO: www.wrp-n.org

THIS research is the leading and pioneering work in the discovery and development of an ultra-sensitive technique for the detection and diagnosis of prion infection using recombinant prion proteins. The significance of an early detection and diagnosis of prion disease, a fatal infection that has no known cure, lies not only in potentially prolonging the lives of many patients through early treatment but saves many human lives by the prevention of its spread. It also can potentially save billions of naira in the food and agricultural industries through the early detection and destruction of infected livestock to prevent the contamination of the healthy ones. The sequential publication of this work in two issues of Nature Methods and the continued multiplication of its numerous citations due to the interest of the global Science Community daily reflected on the Internet proves its popularity among researchers in the fields of infectious diseases and agriculture. The prestige it has brought to the University of Nigeria is best reflected in the acknowledgement and appreciation letter from the editor-in-chief of Nature Methods.

The transmissible spongiform encephalopathies or prion diseases are infectious neuro-degenerative diseases of mammals that include Kreutz-Jakob (CJD) and Kuru diseases in humans, bovine spongiform encephalopathies or Mad Cow Disease in cattle, Scrapie in sheep and Chronic Wasting Disease in Elk. They have also been observed in mink, cats, rodents, exotic engulates and other mammals but not in dogs, rabbits, horses or bird. In humans it exists as CJD or its variant form vCJD which resulted from humans being infected by infected cattle. Transmissible spongiform encephalopathies have incubation periods of months to years, but after the appearance of clinical signs, they are rapidly progressive, untreatable and invariably fatal (Atarashi et al, 2007). Infections can occur from ingestion, inoculation contact with infected surgical materials or body fluids (Onwubiko, H.A. 2012). Transmissible spongiform encephalopathies have been described as the worst way of dying. There are reports of young women going into menopause once infected despite their age, and infected individuals are unable to sleep and at best go into a state of stupor, where they still retain full consciousness (Max, D.T. 2006).

Transmissible spongiform encephalopathies are also making their impact on the world’s agricultural industries. Over four million cattle had been destroyed in Britain alone as a result of prion infection in order to contain its spread to other uninfected cattle and sheep in Europe. Prion diseases are also affecting international commerce, shipping and immigration rules as various nations heighten vigilance and security at their borders and ports to protect their human and livestock populations. Unfortunately in Nigeria there are no strategic plans at present to prevent livestocks or human life from prion infection.

For many years, eminent researchers had sought to know the nature of the disease causing agent of the transmissible spongiform encephalopathies. After having eliminated bacteria, viruses and other micro-organisms, Prusiner in his outstanding Nobel winning work purified the protein components from infected scrapie fibrils and cloned the prion gene (Prusiner et al, 1989). A comparison of the infectiously derived cloned gene showed that it was identical to the host prion gene. Furthermore, other researchers have also cloned the mice and hamster prion gene (Chesebro et al, 1985; Oesh et al, 1985). These workers also found no difference between the normal prion gene and the diseased prion gene. A most convincing proof came with the cloning of the Knock-out mice (mice which lack the prion gene) and the finding that they did not develop prion disease upon infection, (Chesebro, 1998).

How then does the normal prion protein differ from the diseased or infectious prion protein since they are the same protein from the same host gene? The normal prion protein is highly sensitive to protease digestion and is, therefore, designated as PrP-sen (meaning PrP protease sensitive). It is soluble in detergents and present in diverse tissues and cell types. PrP-sen is a monormeric glycophosphatidylinositol (GPI) linked glycoprotein. Its apparent cellular roles include adhesion, differentiation of cells, neuritogenesis, synaptogenesis as well as cell survival.

Free copper is known to be toxic to the central nervous system hence copper levels are mopped up by prion protein which plays a role in their regulation. Also altered sleep patterns and circadian rhythm activity regulated by the penal gland has been observed in mice that lack prions such as the knockout mice (Tobler et al, 1996, 1997). Normal prions (PrP-sen) has also been shown to have super-oxide dismutase activity, thus making it a powerful anti-oxidant for the central nervous system (Brown et al, 1999). Other roles in which normal prion protein (PrP-sen) has been implicated includes signal transduction in neuronal cells which in part may account for the clumsy motor-responses of patients with prion disease (Mouillet-Richard et al, 2000). Normal prion protein has also been implicated in the activation of lymphocytes, a process that may affect patients with prion disease to exhibit an adequate immune response to infections (Li et al 2001). Also evidence from infra red spectroscopy indicate that the normal prion protein (PrP-sen) contains 28% alpha helix and 4% beta pleated sheet.

• To be continued tomorrow.

• Onwubiko is professor of Biochemistry. This an abridged version of his Inaugural Lecture titled “Ultrasensitive Detection of Corrupt Prions and Diagnosis of Their Neurodegenerative Infectious Diseases: Mad Cow Disease in Cattle, Scrapie In Sheep And CJD in Humans” delivered at the University of Nigeria on Thursday, July 9, 2015

Receive News Alerts on Whatsapp: +2348136370421


No Comments yet

Related