Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers.

Giuliana Fusco, Serene W Chen, Philip TF Williamson, Roberta Cascella, Michele Perni, James A Jarvis, Cristina Cecchi, Michele Vendruscolo, Fabrizio Chiti, Nunilo Cremades, Liming Ying, Christopher M Dobson, Alfonso De Simone

OAI: oai:www.repository.cam.ac.uk:1810/296718 • DOI: 10.17863/CAM.43761

Oligomeric species populated during the aggregation process of α-synuclein have been linked to neuronal impairment in Parkinson's disease and related neurodegenerative disorders. By using solution and solid-state nuclear magnetic resonance techniques in conjunction with other structural methods, we identified the fundamental characteristics that enable toxic α-synuclein oligomers to perturb biological membranes and disrupt cellular function; these include a highly lipophilic element that promotes strong membrane interactions and a structured region that inserts into lipid bilayers and disrupts their integrity. In support of these conclusions, mutations that target the region that promotes strong membrane interactions by α-synuclein oligomers suppressed their toxicity in neuroblastoma cells and primary cortical neurons.

Cell Line Tumor Cell Membrane Cerebral Cortex Humans Lipid Bilayers Mutation Neurons Nuclear Magnetic Resonance Biomolecular Parkinson Disease protein aggregation Pathological ALPHA-SYNUCLEIN