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Prions can infect humans and animals, causing Creutzfeldt-Jakob Disease (CJD) in humans, mad cow disease in cattle, and chronic wasting disease of elk and sheep. deer. Infectious and misfolded protein particles are often not detected because they destroy brain tissue, leading to memory loss, mobility problems and ultimately death. Preclinical detection of prions has proven difficult, but new research suggests that skin samples contain early signs of prion disease preceding neurological symptoms.
"Currently, the definitive diagnosis of Creutzfeldt-Jakob disease depends on examination of the brain tissue obtained during a biopsy or autopsy." It was impossible to detect it at the preclinical stage. early, "said Wenquan Zou, MD, PhD, badociate professor of pathology. at the Case Western Reserve University School of Medicine.
In an innovative study published in Nature Communications, Zou and an international team of researchers successfully used two methods to detect prions in skin samples taken from inoculated rodents. This study provides the first proof of concept that readily accessible skin samples could be used to detect prion disease at an early stage, prior to the onset of clinical symptoms.
In the new study, Zou and his colleagues successfully detected prions in rodent skin samples as early as two weeks after the infection. They also detected prions in uninoculated rodent skin lodged next to inoculated cage mates, demonstrating that prion transmission can occur between co-occurring rodents.
Prions were detected in rodent skin samples inoculated before they showed any clinical sign of prion disease. The researchers first inoculated the brain of humanized transgenic hamsters and mice with human or rodent prion samples, respectively. Then they took skin and brain samples at different times and used two different methods to detect prion proteins badociated with diseases in the tissues. In hamsters and mice, researchers detected prions in the skin before they could be detected in brain tissue. The researchers concluded that cutaneous prions could be a useful biomarker for the preclinical diagnosis of prion diseases.
The study compared two methods of highly sensitive prion detection: RT-QuIC (real-time earthquake-induced conversion) and sPMCA (cyclic amplification of misfolded proteins in series). "Both tests were able to efficiently amplify traces of prion protein badociated with the disease found in cutaneous tissue from infected animals," said the study's first author, Zerui Wang, MD, PhD student. at First Hospital of Jilin University, China. in the Zou laboratory. The tests utilize prions in tissue samples as matrix and constituent tissues of the brain or synthetic proteins of the prion as "building blocks" to dramatically increase trace amounts of prions to detectable levels.
One of the methods, RT-QuIC, was used to detect prion particles in symptomatic patients with CJD. However, invasive cerebrospinal fluid (CSF) specimens may be contraindicated in some patients. In addition, "the results of CSF-based prion tests may be uncertain in some cases and all CSF specimens from patients with prion disease are not RT-QuIC positive," he said. Qingzhong Kong, PhD, badociate professor of pathology at Case Western Reserve University School Medicine and co-correspondent author of the study. "Although skin samples do not necessarily replace clbadical swine fever in the routine diagnosis of RT-QuIC-based prion disease, they may be useful in case of suspicion of prion infections, but CPAP is either unavailable or negative for RT-QuIC. "
The results of the study build on previous work by Zou and his colleagues, who showed that skin samples taken at an autopsy taken from patients with prion disease humans had seeding and infectivity of the prions. The next step will be to develop and validate skin prion tests for clinical use.
"As the skin is easily accessible and the skin biopsy is minimally invasive, the detection of cutaneous prions will be very useful for monitoring the course of the disease and evaluating the therapeutic efficacy during clinical or clinical trials. of treatments, when prion treatment will become available in the future. "
Zou and Kong recently received a $ 2.9 million grant from the National Institutes of Health to validate test methods on human skin samples. They will determine whether skin prions could be used as a diagnostic biomarker for CJD or a source of prion transmission.
The researchers believe that the methods could also be adapted to the diagnosis of other diseases involving misfolded proteins. "The sensitive and minimally invasive detection of various misfolded proteins in the skin, such as tau in Alzheimer's disease and alpha-synuclein in Parkinson's disease, could be very useful for the diagnosis of the disease and monitoring its evolution and effectiveness of treatments, "Zou said. "It is possible that the skin eventually serves as a mirror to monitor these misfolded proteins that accumulate and damage the brains of patients with these conditions."
Reference: Wang, Z. et al. "Early preclinical detection of prions in the skin of animals infected with prions." Nature Communications 10: 247 (2019).
Source: Case Western Reserve University School of Medicine
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