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Papers In Press, published online ahead of print April 6, 2006
Department of Physics, University of Genoa, Genoa I-16146
Corresponding Author: relini{at}mail.fisica.unige.it
Dialysis-related amyloidosis (DRA) is characterized by the deposition of insoluble fibrils of
J. Biol. Chem, 10.1074/jbc.M513827200
Submitted on December 28, 2005
Revised on March 13, 2006
Accepted on April 6, 2006
Collagen plays an active role in the aggregation of
2-microglobulin under physio-pathological conditions of dialysis-related amyloidosis
2-microglobulin (2-m) in the musculo-skeletal system. The AFM inspection of ex-vivo amyloid material reveals the presence of bundles of fibrils often associated to collagen fibrils. Aggregation experiments were undertaken in vitro with the aim of reproducing the physio-pathological fibrillation process. To this purpose, atomic force microscopy, fluorescence techniques and NMR were employed. We found that in temperature and pH conditions similar to those occurring in peri-articular tissues in the presence of flogistic processes, 2-m fibrillogenesis takes place in the presence of fibrillar collagen, while no fibrils are obtained without collagen. Moreover, the morphology of 2-m fibrils obtained in vitro in the presence of collagen is extremely similar to that observed in the ex-vivo sample. This result indicates that collagen plays a crucial role in 2-m amyloid deposition under physio-pathological conditions and suggests an explanation to the strict specificity of DRA for the tissues of the skeletal system. We hypothesize that positively charged regions along the collagen fibre could play a direct role in 2-m fibrillogenesis. This hypothesis is sustained by aggregation experiments performed by replacing collagen with a poly-L-lysine-coated mica surface. As shown by NMR measurements, no similar process occurs when poly-L-lysine is dissolved in solution with 2-m. Overall the findings are consistent with the estimates resulting from a simplified collagen model whereby electrostatic effects can lead to high local concentrations of oppositely charged species, such as 2-m, that decay on moving away from the fibre surface.
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