L. Luers, G. Panza, C. Dumpitak, F. Henke, T. Aygenim, D. Willbold, E. Birkmann

Amyloid protein aggregates play a major role in many age-related diseases (Yankner et al., 2008) like Creutzfeldt-Jakob disease (CJD), Alzheimer’s disease, or Parkinson’s disease. Characteristically for these diseases is the aggregation and deposition of certain naturally occurring proteins in the central nervous system. Prion protein (PrP) aggregates can be found in the brain of CJD patients, in case of AD aggregates of amyloid-beta and in PD aggregates of α-synuclein occur. The main event in prion diseases like CJD is the conversion of the native isoform of the prion protein (PrPC) to its disease-related isoform (PrPSc). CJD occurs in three etiologies: spontaneous, genetically caused or by infection. The median age of death for the spontaneous form of CJD (sCJD) is 68 years (Belay and Schonberger 2002), on the contrary the variant CJD (vCJD), which is connected to the consumption of BSE-contaminated meat, and therewith is discussed as infectious case, has a median age of death of 28 years (Belay and Schonberger 2002). Interestingly sCJD correlates with old age whereas vCJD shows no such age-relation. In this context it is a challenging question, why sCJD is age-related, while we know that CJD (in case of vCJD) can also occur in younger individuals. A hypothesis can be that protein aging through chemical modifications known as AGES (Ulrich et al., 2001) may be involved in that mechanism and favour the conversion of the prion protein to the disease related form in elderly individuals. In this context also the M129V polymorphism of the gene (PRNP), which encodes for the prion protein, is particularly interesting. The 129M variant is associated with susceptibility of infection since all registered vCJD cases are homozygous for methionine at codon 129.

Within this work we established an in vitro conversion system (Panza, Stohr et al. 2008; Stohr, Weinmann et al. 2008) for human recPrP, which allows us to analyse the mechanism of amyloid fibril formation. The assay is based on well balanced NaCl and SDS concentrations, which provide a capable environment for de novo fibrillisation of rec PrP monomers. Whilst the latter refers to the spontaneous case of prion diseases, the infectious form is represented by an additional seeding assay. Here we introduced natural PrPSc as seed to accelerate the fibrillisation in the mentioned conversion assay as model system for the infectious case. For our recent studies we used both recombinant variants of the disease-related polymorphism at codon 129 and discussed their differences.

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Panza, G., J. Stohr, et al. (2008). "Spontaneous and BSE-prion-seeded amyloid formation of full length recombinant bovine prion protein." Biochem Biophys Res Commun 373(4): 493-7.

Stohr, J., N. Weinmann, et al. (2008). "Mechanisms of prion protein assembly into amyloid." Proc Natl Acad Sci U S A 105(7): 2409-14.

Ulrich P, Cerami A. (2001). "Protein glycation, diabetes, and aging." Recent Prog Horm Res. 56:1-21.

Yankner BA, Lu T, Loerch P. (2008). "The aging brain." Annu Rev Pathol. 3:41-66

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