TY - JOUR
T1 - Mutant PrPCJD prevails over wild-type PrPCJD in the brain of V210I and R208H genetic Creutzfeldt-Jakob disease patients
AU - Cardone, Franco
AU - Principe, Serena
AU - Schininà, Maria Eugenia
AU - Maras, Bruno
AU - Capellari, Sabina
AU - Parchi, Piero
AU - Notari, Silvio
AU - Di Francesco, Laura
AU - Poleggi, Anna
AU - Galeno, Roberta
AU - Vinci, Ramona
AU - Mellina, Vittorio
AU - Almonti, Susanna
AU - Ladogana, Anna
AU - Pocchiari, Maurizio
PY - 2014/11/14
Y1 - 2014/11/14
N2 - Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder characterized by the deposition of the pathological conformer (PrPCJD) of the host encoded cellular prion protein (PrPC). In genetic CJD associated with V210I or R208H PrP substitutions, the pathogenic role of mutant residues is still poorly understood. To understand how V210I or R208H PrP mutations facilitate the development of the disease, we determined by mass spectrometry the quantitative ratio of mutant/wild-type PrPCJD allotypes in brains from affected subjects. We found that the mutant PrPCJD allotypes moderately exceeds of 2- or 3-fold the amount of the wild-type counterpart suggesting that these mutations mainly exert their pathogenic effect on the onset of the pathogenic cascade. Different mechanisms can be hypothesized to explain the pathogenic role of mutant residues: V210I and R208H substitutions can increase the concentration of PrPC and the probability to form insoluble aggregates, or they may facilitate the formation of pathological intermediates, or, alternatively, they may increase the affinity for ligands that are involved in the initial phases of PrPCJD formation and aggregation. Whatever the mechanism, the enrichment found for the mutated PrPCJD species indicates that these altered structures are more prone, with respect to the non-mutated ones, to be captured in the polymerization process either at the onset or during the development of the disease.
AB - Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder characterized by the deposition of the pathological conformer (PrPCJD) of the host encoded cellular prion protein (PrPC). In genetic CJD associated with V210I or R208H PrP substitutions, the pathogenic role of mutant residues is still poorly understood. To understand how V210I or R208H PrP mutations facilitate the development of the disease, we determined by mass spectrometry the quantitative ratio of mutant/wild-type PrPCJD allotypes in brains from affected subjects. We found that the mutant PrPCJD allotypes moderately exceeds of 2- or 3-fold the amount of the wild-type counterpart suggesting that these mutations mainly exert their pathogenic effect on the onset of the pathogenic cascade. Different mechanisms can be hypothesized to explain the pathogenic role of mutant residues: V210I and R208H substitutions can increase the concentration of PrPC and the probability to form insoluble aggregates, or they may facilitate the formation of pathological intermediates, or, alternatively, they may increase the affinity for ligands that are involved in the initial phases of PrPCJD formation and aggregation. Whatever the mechanism, the enrichment found for the mutated PrPCJD species indicates that these altered structures are more prone, with respect to the non-mutated ones, to be captured in the polymerization process either at the onset or during the development of the disease.
KW - Amyloidogenesis
KW - gCJD
KW - PrP allotypes
KW - PrP
KW - Quantitative MS
KW - TSE
UR - http://www.scopus.com/inward/record.url?scp=84909996662&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84909996662&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2014.10.051
DO - 10.1016/j.bbrc.2014.10.051
M3 - Article
C2 - 25450391
AN - SCOPUS:84909996662
VL - 454
SP - 289
EP - 294
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 2
ER -