A novel human disease with abnormal prion protein sensitive to protease

Pierluigi Gambetti, Zhiqian Dong, Jue Yuan, Xiangzhu Xiao, Mengjie Zheng, Amer Alshekhlee, Rudy Castellani, Mark Cohen, Marcelo A Barria, D Gonzalez-Romero, Ermias D Belay, Lawrence B Schonberger, Karen Marder, Carrie Harris, James R Burke, Thomas Montine, Thomas Wisniewski, Dennis W Dickson, Claudio Soto, Christine M HuletteJames A Mastrianni, Qingzhong Kong, Wen-Quan Zou

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

OBJECTIVE: To report a novel prion disease characterized by distinct histopathological and immunostaining features, and associated with an abnormal isoform of the prion protein (PrP) that, contrary to the common prion diseases, is predominantly sensitive to protease digestion.

METHODS: Eleven subjects were investigated at the National Prion Disease Pathology Surveillance Center for clinical, histopathological, immunohistochemical, genotypical, and PrP characteristics.

RESULTS: Patients presented with behavioral and psychiatric manifestations on average at 62 years, whereas mean disease duration was 20 months. The type of spongiform degeneration, the PrP immunostaining pattern, and the presence of microplaques distinguished these cases from those with known prion diseases. Typical protease-resistant PrP was undetectable in the cerebral neocortex with standard diagnostic procedures. After enrichment, abnormal PrP was detected at concentrations 16 times lower than common prion diseases; it included nearly 4 times less protease-resistant PrP, which formed a distinct electrophoretic profile. The subjects examined comprised about 3% of sporadic cases evaluated by the National Prion Disease Pathology Surveillance Center. Although several subjects had family histories of dementia, no mutations were found in the PrP gene open reading frame.

INTERPRETATION: The distinct histopathological, PrP immunohistochemical, and physicochemical features, together with the homogeneous genotype, indicate that this is a previously unidentified type of disease involving the PrP, which we designated "protease-sensitive prionopathy" (or PSPr). Protease-sensitive prionopathy is not rare among prion diseases, and it may be even more prevalent than our data indicate because protease-sensitive prionopathy cases are likely also to be classified within the group of non-Alzheimer's dementias.

Original languageEnglish
Pages (from-to)697-708
Number of pages12
JournalAnnals of Neurology
Issue number6
Publication statusPublished - Jun 2008

Keywords / Materials (for Non-textual outputs)

  • Age of Onset
  • Aged
  • Brain
  • DNA Mutational Analysis
  • Dementia
  • Disease Progression
  • Female
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Genotype
  • Humans
  • Immunohistochemistry
  • Incidence
  • Inclusion Bodies
  • Male
  • Middle Aged
  • Nerve Degeneration
  • Neurons
  • Peptide Hydrolases
  • Prion Diseases
  • Prions


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