Structural Determinants of Phenotypic Diversity and Replication Rate of Human Prions


Sporadic Creutzfeldt-Jakob disease (sCJD) represents ~90% of all human prion diseases worldwide. This neurodegenerative disease, which is transmissible and invariably fatal, is characterized by variable progression rates and remarkable diversity of clinical and pathological traits. The infectious sCJD prions propagating the pathology mainly in the brain are assemblies of abnormally folded isoform (PrPSc) of a host-encoded prion protein (PrPC). The structure and replication mechanisms of human prions are unknown, and whether the PrPSc subtypes identified by proteolytic fragmentation represent distinct strains of sCJD prions has been debated. Here, we isolated sCJD prions from patients with two very distant phenotypes of the disease, compared their structural organization using recently developed biophysical techniques, and investigated their replication in vitro. Our data indicate that these sCJD prions are characterized by different secondary structure organization and quaternary packing arrangements, and that these structural differences are responsible for distinct prion replication rates and unique phenotypic characteristics of the disease. Furthermore, our analysis reveals that, contrary to previous observations for yeast prions, the replication tempo of sCJD prions is determined not so much by their conformational stability but by specific structural features that control the growth speed of prion particles.


Vyšlo v časopise: Structural Determinants of Phenotypic Diversity and Replication Rate of Human Prions. PLoS Pathog 11(4): e32767. doi:10.1371/journal.ppat.1004832
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1004832

Souhrn

Sporadic Creutzfeldt-Jakob disease (sCJD) represents ~90% of all human prion diseases worldwide. This neurodegenerative disease, which is transmissible and invariably fatal, is characterized by variable progression rates and remarkable diversity of clinical and pathological traits. The infectious sCJD prions propagating the pathology mainly in the brain are assemblies of abnormally folded isoform (PrPSc) of a host-encoded prion protein (PrPC). The structure and replication mechanisms of human prions are unknown, and whether the PrPSc subtypes identified by proteolytic fragmentation represent distinct strains of sCJD prions has been debated. Here, we isolated sCJD prions from patients with two very distant phenotypes of the disease, compared their structural organization using recently developed biophysical techniques, and investigated their replication in vitro. Our data indicate that these sCJD prions are characterized by different secondary structure organization and quaternary packing arrangements, and that these structural differences are responsible for distinct prion replication rates and unique phenotypic characteristics of the disease. Furthermore, our analysis reveals that, contrary to previous observations for yeast prions, the replication tempo of sCJD prions is determined not so much by their conformational stability but by specific structural features that control the growth speed of prion particles.


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