Protease-sensitive prionopathy (PSPr) is a neurodegenerative disorder caused by an abnormal isoform of the prion protein. Contrary to the prions in Creutzfeldt–Jakob disease (CJD), the prions in this condition are sensitive to protease activity.
was first described in an abstract for a conference on prions in 2006, and this study was published in a 2008 report on 11 cases. The study was conducted by Gambetti P., Zou W.Q., and coworkers from the United States National Prion Disease Pathology Surveillance Center.
Symptoms of PSPr are behavioral and psychiatric abnormalities with progressive decline in cognitive and motor functions (including dementia, ataxia, parkinsonism, psychosis, aphasia and mood disorders). This is similar to what occurs in other spongiform encephalopathies, and the condition can be mistaken for Alzheimer's dementia.
Contrary to what is the case in CJD, there were no cases with a positive 14-3-3 protein test in the cerebrospinal fluid, no periodic complexes on electroencephalography (EEG), and no pathognomonic changes on diffusion-weighted magnetic resonance images. The mean age of onset in the original 11 patients was 62 years. Patients progressed to death in 20 months on average. PSPr accounted for three percent of prion disease cases evaluated by the U.S. National Prion Disease Pathology Surveillance Center (prion diseases occur in the order of magnitude of 1 case per million people).
The diagnosis can be made on pathological examination. There are unique microscopic and immunohistochemical features, and the prions cannot be digested using proteases. Because 8 out of 10 patients had a positive family history of dementia in the original study, a genetic cause was suspected. Although all cases were homozygous for valine at codon 129 of the PrP gene, no mutations were detected.
Although the protease-resistant pathological prion protein (PrPSc, a hallmark of prion disease) is virtually undetectable by conventional Western blotting with the widely used anti-PrP antibody 3F4, PSPr exhibits a unique PrPSc gel profile on Western blotting probing with another anti-PrP antibody 1E4. In 2010, it was demonstrated that PSPr affects not only patients carrying PrP-129 Val/Val polymorphism but also patients carrying PrP-129Met/Met or PrP-129Met/Val. Moreover, the amount of protease-resistant PrPSc is found to be variable due to the involvement of Met at residue 129 of PrP; as a result, the term "PSPr" has been changed to variably protease-sensitive prionopathy (VPSPr).
How these protease-resistant prions lead to neurological disease remains incompletely understood. For instance, protein-resistant prions have been found in normal human brains.