Parkinson’s disease is associated with the conversion of the soluble protein -synuclein into protein aggregates (Lewy bodies) accumulating in the cytosol of dopaminergic neurons of the brain. We have isolated five species of the protein including the monomer (M), nontoxic type A* oligomers (OA*), toxic type B* oligomers (OB*), short (SF) and long (LF) fibrils. By using solution and solid-state NMR techniques and other biophysical techniques, we have identified the fundamental structural characteristics that enable toxic OB* oligomers, unlike OA*, to perturb biological membranes and generate cellular toxicity. We have then compared the evolution in time of six distinct readouts of cellular dysfunction in neuroblastoma cells and primary neurons, identifying the most toxic species and the time scale of the various events in the toxicity process. SF and LF induced the same cascade of toxic events as OB*, but slowly due to their ability to release slowly small oligomers close to OB*, which were observed to interact and cross neuronal membranes. We will finally show the ability of a small molecule called squalamine, which is currently under a phase II clinical trial to cure Parkinson’s disease, to inhibit the membrane-induced aggregation of alpha-synuclein and prevent the OB* interaction with biological membranes.
29 maggio
The seminar will be held by Prof. Fabrizio Chiti of the Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche
Università degli Studi di Firenze, Firenze, in room A (building CU010) at 13:00.