Infectious prion protein discovered in urine of patients with variant Creutzfeldt-Jakob disease

Claudio Soto, Ph.D., in one of his labs at The University of Texas Health Science Center at Houston (UTHealth). Credit: Image courtesy of University of Texas Health Science Center at Houston

The misfolded and infectious prion protein that is a marker for variant Creutzfeldt-Jakob disease – linked to the consumption of infected cattle meat – has been detected in the urine of patients with the disease by researchers at The University of Texas Health Science Center at Houston (UTHealth) Medical School.

The results of the international study, led by Claudio Soto, Ph.D., professor of neurology at the UTHealth Medical School, will be published in the Aug. 7 issue of the New England Journal of Medicine.

Variant Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in animals – also known as Mad Cow disease – are fatal neurodegenerative disorders. There are currently no noninvasive tools available to diagnose the disease and there are no treatments.

Sporadic Creutzfeldt-Jakob disease occurs worldwide at a rate of around 1 new case per million people per year. The variant form is a new disease occurring in people who either ate the beef of cows with bovine spongiform encephalopathy or, in the case of three patients in the United Kingdom, received blood transfusions from asymptomatic infected donors.

The international team of researchers analyzed urine samples from 68 patients with sporadic Creutzfeldt-Jakob disease, 14 patients with variant Creutzfeldt-Jakob disease, four patients with genetic prion diseases, 50 patients with other neurodegenerative diseases, 50 patients with nondegenerative neurologic diseases and 52 healthy persons.

Soto’s laboratory used a protein misfolding cyclic amplification assay, invented in the lab, which mimics the prion replication process in vitro that occurs in prion disease. The misfolded prion proteins were detected in the urine of 13 of 14 patients with variant Creutzfeldt-Jakob disease. The single patient whose urine was negative had been receiving an experimental treatment of pentosan polysulfate directly into the brain. No misfolded prion proteins were detected in the urine of any the other study subjects, including the patients who had sporadic Creutzfeldt-Jakob disease.

“What could be less invasive than detecting this disease in urine? The fact that we were able to detect just the variant Creutzfeldt-Jakob disease form in the urine is very important. This could lead to the development of commercial technology for diagnosis as well as to determine the safety of donated blood and urinary products,” said Soto, who is the director of The George and Cynthia Mitchell Center for Research in Alzheimer’s disease and Related Brain Disorders, and founder of Amprion Inc, a biotech company developing the cyclic amplification technology for commercial application.

According to the World Health Organization (WHO), variant Creutzfeldt-Jakob disease affects younger patients, who have a median age of 28 at death, compared to sporadic Creutzfeldt-Jakob disease with a median age of 68. Most patients, after diagnosis of either form, live less than a year before death.

As of June 2, 2014, 177 of 229 people in the world with Creutzfeldt-Jakob disease were from the United Kingdom. A 2013 study published in the British Medical Journal has estimated that approximately 30,000 people in the United Kingdom might be carriers of the variant form of the disease.

“This study reports, for the first time, the detection of the abnormal prion protein in the urine from patients with variant Creutzfeldt-Jakob disease using the protein misfolding amplification technique pioneered by Dr. Claudio Soto,” said co-author James W. Ironside, FMedSci, FRSE, professor of clinical neuropathology at the National CJD Research and Surveillance Unit at the University of Edinburgh. “This has great potential to allow the development of a highly sensitive and specific non-invasive test that can be used for the diagnosis of variant Creutzfeldt-Jakob disease, and potentially as a screening tool for variant Creutzfeldt-Jakob disease infection in asymptomatic individuals, which is a topic of current interest in the United Kingdom.”

Source: University of Texas Health Science Center at Houston

Scrapie could breach the species barrier

Scrapie is a neurodegenerative disease that has been known for centuries and which affects sheep and goats. Credit: INRA/Florent Giffard

INRA scientists have shown for the first time that the pathogens responsible for scrapie in small ruminants (prions) have the potential to convert the human prion protein from a healthy state to a pathological state. In mice models reproducing the human species barrier, this prion induces a disease similar to Creutzfeldt-Jakob disease. These primary results published in Nature Communications on 16 December 2014, stress the necessity to reassess the transmission of this disease to humans.

Scrapie is a neurodegenerative disease that has been known for centuries and which affects sheep and goats. Similar to Bovine Spongiform Encephalopathy (BSE) or mad cow disease, scrapie is caused by a transmissible pathogen protein called prion.

However, and contrary to BSE[1], epidemiological studies have never been able to establish a link between this disease and the occurrence of prion diseases in humans. "Risks of transmitting scrapie to humans (zoonose) were hitherto considered negligible because of the species barrier that naturally prevents prion propagation between species," said Olivier 

Andreoletti, INRA scientist who led the present study.

Researchers at INRA studied the permeability of the human transmission barrier to pathogens responsible for scrapie, using animal models specifically developed for this purpose. This approach previously allowed the confirmation of the zoonotic nature of prions responsible for BSE in cows and of the variant of Creutzfeldt-Jakob disease in humans (vCJD).

Unexpectedly, in these rodent models, certain pathogens responsible for scrapie were able to cross the transmission barrier. Moreover, the pathogens that propagated through this barrier were undistinguishable from the prions causing the sporadic form of Creutzfeldt-Jakob disease (sCJD). This data suggest a potential link between the occurrence of certain sCJD and these animal prions.

"Since CJD is scarce, about 1 case per million and per year, and incubation periods are usually long -several decades- it is extremely difficult for epidemiological studies to try and make this link," explains Olivier Andreoletti.

In their conclusions, the authors stress the fact that CJD cases are rare though scrapie has been circulating for centuries in small ruminants for which we eat the meat. Even if in future studies scrapie is finally confirmed to have a zoonotic potential, the authors consider that this disease does not constitute a new major risk for public health.

Source: INRA-France