Allelic origin of the abnormal prion protein isoform in familial prion diseases

Shu G. Chen, Piero Parchi, Paul Brown, Sabina Capellari, Wenquan Zou, Elizabeth J. Cochran, Cindy L. Vnencak-Jones, Jean Julien, Claude Vital, Jacqueline Mikol, Elio Lugaresi, Lucila Autilio-Gambetti, Pierluigi Gambetti

Research output: Contribution to journalArticlepeer-review


The hallmark of prion diseases is the presence of an aberrant isoform of the prion protein (PrP(res)) that is insoluble in nondenaturing detergents and resistant to proteases. We investigated the allelic origin of PrP(res) in brains of subjects heterozygous for the D178N mutation linked to fatal familial insomnia (FFI) and a subtype of Creutzfeldt-Jakob disease (CJD178) as well as for insertional mutations associated with another CJD subtype. We found that in FFI and CJD178 subjects, only mutant PrP was detergent-insoluble and protease-resistant. Therefore, PrP(res) derives exclusively from the mutant allele carrying the D178N mutation. In contrast, in the CJD subtype harboring insertional mutations, wild-type PrP was also detergent-insoluble and likely to be protease-resistant. Our findings indicate that the participation of the wild-type PrP in the formation of PrP(res) depends on the type of mutations, providing an insight into the molecular mechanisms underlying the phenotypic heterogeneity in familial prion diseases.

Original languageEnglish
Pages (from-to)1009-1015
Number of pages7
JournalNature Medicine
Issue number9
Publication statusPublished - Sep 1997

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)


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