Gerstmann-Sträussler-Scheinker disease revisited: accumulation of covalently-linked multimers of internal prion protein fragments

Laura Cracco, Xiangzhu Xiao, Satish K. Nemani, Jody Lavrich, Ignazio Cali, Bernardino Ghetti, Silvio Notari, Witold K. Surewicz, Pierluigi Gambetti

Research output: Contribution to journalArticle

7 Scopus citations


Despite their phenotypic heterogeneity, most human prion diseases belong to two broadly defined groups: Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker disease (GSS). While the structural characteristics of the disease-related proteinase K-resistant prion protein (resPrPD) associated with the CJD group are fairly well established, many features of GSS-associated resPrPD are unclear. Electrophoretic profiles of resPrPD associated with GSS variants typically show 6-8 kDa bands corresponding to the internal PrP fragments as well as a variable number of higher molecular weight bands, the molecular nature of which has not been investigated. Here we have performed systematic studies of purified resPrPD species extracted from GSS cases with the A117V (GSSA117V) and F198S (GSSF198S) PrP gene mutations. The combined analysis based on epitope mapping, deglycosylation treatment and direct amino acid sequencing by mass spectrometry provided a conclusive evidence that high molecular weight resPrPD species seen in electrophoretic profiles represent covalently-linked multimers of the internal ~ 7 and ~ 8 kDa fragments. This finding reveals a mechanism of resPrPD aggregate formation that has not been previously established in prion diseases.

Original languageEnglish (US)
Pages (from-to)85
Number of pages1
JournalActa Neuropathologica Communications
Issue number1
StatePublished - May 29 2019


  • Aggregate formation
  • Creutzfeldt-Jakob disease
  • Epitope mapping
  • Mass spectrometry
  • Multimers
  • Prion protein

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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