University of Cambridge > Talks.cam > Biophysical Seminars > Protein Misfolding Diseases. The Structural Determinants of Protein Misfolded Oligomers Responsible for Toxicity and the Mechanism through which Toxicity is Mediated

Protein Misfolding Diseases. The Structural Determinants of Protein Misfolded Oligomers Responsible for Toxicity and the Mechanism through which Toxicity is Mediated

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The conversion of proteins from their native state to highly structured fibrillar deposits is associated with a number of neurodegenerative diseases. In these diseases a key role is played by the protein oligomer species that form as intermediate species or are released by mature fibrils. Such species are indeed highly toxic as they are able to interact with cellular targets and cause cell dysfunction. The structural factors responsible for protein oligomer toxicity and the mechanism of such toxicity will be described, taking advantage of three pairs of toxic and nontoxic oligomers from three different protein systems, namely the amyloid β associated with Alzheimer’s disease, α-synuclein associated with Parkinson’s disease and the model protein HypF-N from E. coli. The use of a number of readouts of cell toxicity and of their time courses revealed the key events of the interaction between oligomers and biological membranes and the sequence of events in the toxicity cascade, establishing that the destabilization of the cell membrane with a Ca2+ influx is an early insult cause by the oligomers. Given the importance of an altered calcium homeostasis in cells exposed to protein misfolded oligomers we have tried to identify the mechanism through which this homeostasis is compromised and the calcium channels responsible for the abnormal calcium influx.

This talk is part of the Biophysical Seminars series.

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