Prions impair bioaminergic functions through serotonin- or catecholamine-derived neurotoxins in neuronal cells.
The conversion of the cellular prion protein, PrP(C), to an abnormal isoform, PrP(Sc), is a central event leading to neurodegeneration in prion diseases. Deciphering the molecular and cellular changes imparted by PrP(Sc) accumulation remains an arduous task due to the small number of cell lines supporting prion replication. Here we introduce the 1C11 cell line as a new in vitro model to investigate prion pathogenesis. This cell line is a committed neuroectodermal progenitor able to differentiate into fully functional serotonergic or catecholaminergic neurons. 1C11 cells, which naturally express PrP(C) from the undifferentiated state, can be chronically infected with various prion strains. Prion infection does not promote any noticeable phenotypic change in the progenitor cells nor prevent the onset of the serotonergic and catecholaminergic differentiation programs. Pathogenic prions, however, deviate the overall neurotransmitter-metabolism in both pathways by decreasing bioamine synthesis, storage, and transport, and enhancing catabolism. Noteworthy, oxidized derivatives of both serotonin and catecholamines are selectively detected in the differentiated progenies of infected cells and contribute to irreversible impairment in bioamine synthesis. Finally, the level of PrP(Sc) accumulation, that of infectivity, and the extent of all prion-induced changes in infected cells appear to be correlated. The report of such specific effects of infection on neuronal functions provides a foundation for dissecting the events underlying loss of neuronal homeostasis in prion diseases.
Mouillet-Richard
Sophie
S
Différenciation Cellulaire et prions, CNRS FRE 2937, Institut Pasteur, INSERM U747, 7 rue Guy Môquet, Villejuif, France. mouillet@vjf.cnrs.fr
Nishida
Noriyuki
N
Pradines
Elodie
E
Laude
Hubert
H
Schneider
Benoît
B
Féraudet
Cécile
C
Grassi
Jacques
J
Launay
Jean-Marie
JM
Lehmann
Sylvain
S
Kellermann
Odile
O
D000818:Animals; D002395:Catecholamines / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism*; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012701:Serotonin / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology
D002395:Catecholamines; D009498:Neurotoxins; D018621:PrPC Proteins; D018620:PrPSc Proteins; D012701:Serotonin