Fundamental research Experimental models

RAIPNHB

Risk Assessment of insoluble PrP from normal human brains

2009: 1 year / Grant: 20 000 euros

Project: The critical molecular event in the initiation of the pathogenesis of prion diseases, are poorly understood, in particular for sporadic diseases. Based on some previous data showing the existence ofsmall amounts of detergent-insoluble PrP aggregates and PK-resistant PrP species(iPrP) in uninfected human and animal brains, the project RAINHP proposed to investigate the conversion pathways of PrPC into PrPTSE.

Main results and related published data: The presence of iPrP wasfirst explored in cellcultures over-expressing PrP mutant involved in familial prion diseases: PrPT183A of PrPF198S that affect Nglycosylation.
The intracellular expression of PrPT183A allowed an increase in the formation of iPrP in intracellularcompartment. Moreover, PK resistant PrP could be identified in the absence of mutated PrP, only when using the 1E4 antibody with a singular glycoform ratio, but not with 3F4 antibody. In this project, it was also reported an adaptation of the technicto brain from AD patients. Aggregated forms of huPrP and A 42 were shown to be co-purified from brain extracts of AD brains confirming thusthe interaction between these two molecules. Moreover, in human AD brain, an anti-PrP antibody and the Gene5protein specifically binds to insoluble PrP (iPrP) and co-precipitate insoluble A . In addition this work contributed to further project concerning protease sensitive prionopathy (PSPr) that they renamed “variably PSPr” (VPSPr) which is different from typical prion diseases.