Molecular Structure of Amyloid Fibrils Controls the Relationship between Fibrillar Size and ToxicityReport as inadecuate




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Background

According to the prevailing view, soluble oligomers or small fibrillar fragments are considered to be the most toxic species in prion diseases. To test this hypothesis, two conformationally different amyloid states were produced from the same highly pure recombinant full-length prion protein rPrP. The cytotoxic potential of intact fibrils and fibrillar fragments generated by sonication from these two states was tested using cultured cells.

Methodology-Principal Findings

For one amyloid state, fibril fragmentation was found to enhance its cytotoxic potential, whereas for another amyloid state formed within the same amino acid sequence, the fragmented fibrils were found to be substantially less toxic than the intact fibrils. Consistent with the previous studies, the toxic effects were more pronounced for cell cultures expressing normal isoform of the prion protein PrPC at high levels confirming that cytotoxicity was in part PrPC-dependent. Silencing of PrPC expression by small hairpin RNAs designed to silence expression of human PrPC shRNA-PrPC deminished the deleterious effects of the two amyloid states to a different extent, suggesting that the role of PrPC-mediated and PrPC-independent mechanisms depends on the structure of the aggregates.

Conclusions-Significance

This work provides a direct illustration that the relationship between an amyloid-s physical dimension and its toxic potential is not unidirectional but is controlled by the molecular structure of prion protein PrP molecules within aggregated states. Depending on the structure, a decrease in size of amyloid fibrils can either enhance or abolish their cytotoxic effect. Regardless of the molecular structure or size of PrP aggregates, silencing of PrPC expression can be exploited to reduce their deleterious effects.



Author: Young Jin Lee, Regina Savtchenko, Valeriy G. Ostapchenko, Natallia Makarava, Ilia V. Baskakov

Source: http://plos.srce.hr/



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