Structure and membrane interaction of amyloidogenic proteins in Alzheimer's and Parkinson's disease

Abstract : The misfolding and deposition of amyloidogenic proteins are features commonly associated with neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. Membrane interaction of these proteins is thought to be important for pathogenesis and the normal physiological function of α-synuclein but the mechanisms by which membrane interaction causes toxicity remain poorly understood. The focus of this talk will be on my recent work that has revealed a novel mechanism by which α-synuclein can induce membrane curvature in a concentration-dependent manner. This process results in tubular or small spherical membrane deformations and causes a potentially toxic disruption of membrane integrity. Imaging of giant unilamellar vesicles showed that curvature induction is caused by α-synuclein molecules that cluster on the membrane. This data illustrate the importance of a high local protein density for the induction of membrane curvature and suggest that pre-formed oligomers will be even more potent at disrupting membranes. Analogous mechanisms for the potentially toxic disruption of membrane integrity can be applied to other amyloidogenic proteins, such as Aβ and amylin. Hence, one of my central hypotheses is that oligomers can act as a delivery vehicle to locally saturate membranes with membrane curvature inducing amyloidogenic proteins, and that this interaction causes loss of membrane integrity.