A novel form of human disease with a protease-sensitive prion protein and heterozygosity methionine/valine at codon 129: Case report

Abstract

BackgroundSporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder in humans included in the group of Transmissible Spongiform Encephalopathies or prion diseases. The vast majority of sCJD cases are molecularly classified according to the abnormal prion protein (PrPSc) conformations along with polymorphism of codon 129 of the PRNP gene. Recently, a novel human disease, termed "protease-sensitive prionopathy", has been described. This disease shows a distinct clinical and neuropathological phenotype and it is associated to an abnormal prion protein more sensitive to protease digestion.Case presentationWe report the case of a 75-year-old-man who developed a clinical course and presented pathologic lesions compatible with sporadic Creutzfeldt-Jakob disease, and biochemical findings reminiscent of "protease-sensitive prionopathy". Neuropathological examinations revealed spongiform change mainly affecting the cerebral cortex, putamen/globus pallidus and thalamus, accompanied by mild astrocytosis and microgliosis, with slight involvement of the cerebellum. Confluent vacuoles were absent. Diffuse synaptic PrP deposits in these regions were largely removed following proteinase treatment. PrP deposition, as revealed with 3F4 and 1E4 antibodies, was markedly sensitive to pre-treatment with proteinase K. Molecular analysis of PrPSc showed an abnormal prion protein more sensitive to proteinase K digestion, with a five-band pattern of 28, 24, 21, 19, and 16 kDa, and three aglycosylated isoforms of 19, 16 and 6 kDa. This PrPSc was estimated to be 80% susceptible to digestion while the pathogenic prion protein associated with classical forms of sporadic Creutzfeldt-Jakob disease were only 2% (type VV2) and 23% (type MM1) susceptible. No mutations in the PRNP gene were found and genotype for codon 129 was heterozygous methionine/valine.ConclusionsA novel form of human disease with abnormal prion protein sensitive to protease and MV at codon 129 was described. Although clinical signs were compatible with sporadic Creutzfeldt-Jakob disease, the molecular subtype with the abnormal prion protein isoforms showing enhanced protease sensitivity was reminiscent of the "protease-sensitive prionopathy". It remains to be established whether the differences found between the latter and this case are due to the polymorphism at codon 129. Different degrees of proteinase K susceptibility were easily determined with the chemical polymer detection system which could help to detect proteinase-susceptible pathologic prion protein in diseases other than the classical ones.

Experimental Transmission of the Chronic Wasting Disease Agent to Swine after Oral or Intracranial Inoculation

“…To investigate possible biochemical properties of PrP Sc that may have contributed to the variation in aggregation kinetics observed in the RT-QuIC assay, the EIA optical density of matched samples was measured with and without treatment with proteinase K (PK). The difference in optical density between non-PK-treated and PK-treated samples allows us to estimate the relative PK resistance of the PrP Sc present in the brains of infected pigs (40).…”

“…Sensitivity to PK was determined by the EIA protocol described above but with the addition of a pretesting PK treatment step (40). Briefly, for each animal, two 100-l aliquots of 20% (wt/vol) brain homogenate were prepared; 5 l of 1 mg/ml PK (USB Corporation, Cleveland, OH, USA) was added to one aliquot, and 5 l of PBS was added to the second aliquot.…”

Variably Protease-Sensitive Prionopathy: a Novel Disease of the Prion Protein

“…Currently, a total of 30 cases of VPSPr have been published (Head et al 2009Jansen et al 2010;Rodríguez-Martínez et al 2010;Zou et al 2010a). These 30 cases are not equally distributed among the three 129 genotypes: 19 are Val/Val, 8 are Met/Val, and 3 are Met/Met.…”

Modeling Amyloid Diseases in Fruit Fly Drosophila Melanogaster

“…However, increasing evidence argues against the neurotoxicity of PrP Sc . Significant pathology and/or clinical dysfunction develop with little accumulation of PrP Sc [Flechsig et al, 2000;Manson et al, 1999] and some familial prion diseases are not transmissible, and are not accompanied by the accumulation of protease resistant PrP [Brown et al, 1994;Rodríguez-Martínez et al, 2010;Tateishi & Kitamoto, 1995;Zou et al, 2010]. Thus, it is not clear whether specific conformers are associated with neuronal dysfunction and degeneration [Solomon et al, 2010].…”