Accessing transmissibility and diagnostic marker of skin prions.
Kong, Qingzhong Safar, Jiri G. Zou, Wen-Quan
Case Western Reserve University, Cleveland, OH, United States
Abstract The fatal, transmissible animal and human prion diseases are characterized by the deposition in the brain of a proteinase K (PK)-resistant infectious prion protein (PrPSc), an isoform derived from the cellular protein (PrPC) through misfolding. A definitive antemortem diagnosis is virtually impossible for most patients because of the difficulty in obtaining the brain tissues by biopsy. Recently, PrPSc has been reported to be detected in the skin of experimentally or naturally scrapie-infected animals (Thomzig et al., 2007). Consistent with this finding, we have observed PK-resistant PrP in the skin of a patient with variant Creutzfeldt-Jakob disease (vCJD), an acquired form of human prion disease caused by bovine prion (Notari et al., 2010). Unexpectedly, our latest preliminary study identified two types of PK-resistant PrP molecules [with gel mobility similar to the PrPSc types 1 and 2 from the brain of sporadic CJD (sCJD)] in the fibroblast cells extracted from the skin of clinical sCJD patients and asymptomatic subjects carrying PrP mutations linked to familial CJD (fCJD). We also detected PrPSc in the skin of humanized transgenic (Tg) mice inoculated intracerebrally with a human prion. Moreover, prion infectivity has been observed in the skin of infected greater kudu (Cunningham et al., 2004) and a murine prion inoculated to mice via skin scarification can not only propagate in the skin, but also spread to the brain to cause prion disease (Wathne et al., 2012). We hypothesize that the skin of patients with prion disease harbors prion infectivity and the presence of PK-resistant PrP in the skin is a novel diagnostic marker for preclinical CJD patients. To test the hypotheses, we propose to (1) determine prion infectivity of the skin- derived fibroblasts and skin of sCJD patients and asymptomatic PrP-mutation carriers using humanized Tg mouse bioassay, (2) to pinpoint the earliest stage at which PrPSc becomes detectable in the skin of prion- infected Tg mice, and (3) to detect PrPSc in the skin of various human prion diseases, using conventional as well as highly sensitive RT-QuIC assays for both (2) and (3). If successful, our proposal may not only help prevent potential transmission of human prion diseases but also enable definitive and less intrusive antemortem diagnosis of prion diseases. Finally, knowledge generated from this study may also enhance our understanding of other neurodegenerative diseases such as Alzheimer's disease.
Public Health Relevance Currently it is unclear whether or not the skin of patients with prion diseases is infectious and, moreover, there is no alternative preclinical definitive testing or the brain biopsy in the prion diseases. The aim of our proposal is to address the issues by detection of the infectivity of patients' skin samples using animal bioassay and a new highly sensitive RT-QuIC assay. We believe that our study will not only provide insights into the pathogenesis and transmissibility of prion disease but also will develop preclinical definitive testing for prion disease.
Funding Agency Agency National Institute of Health (NIH)
Institute National Institute of Neurological Disorders and Stroke (NINDS)
Type Exploratory/Developmental Grants (R21)
Project # 1R21NS096626-01
Application # 9092119
Study Section Special Emphasis Panel (ZRG1)
Program Officer Wong, May Project Start 2016-02-01
Project End 2018-01-31
Budget Start 2016-02-01
Budget End 2017-01-31
Support Year 1
Fiscal Year 2016
Indirect Cost Institution Name Case Western Reserve University
Type Schools of Medicine
DUNS # 077758407
Country United States
Zip Code 44106
Tuesday, May 10, 2016
2015 PDA Virus & TSE Safety Forum Meeting Report
>>>Recently transmission of prions from blood of patients with sporadic CJD to humanized mice could be demonstrated.<<<
>>>Further-on, urine samples of a control population (normal and neurological population) showed no signal in the study; *** however, in samples from patients with sporadic CJD and vCJD, a signal was detected in both patient populations.<<<
Meeting Report: 2015 PDA Virus & TSE Safety Forum
Terry S. Singeltary Sr.