Instituto de Biologı́a Molecular y Celular de Rosario,

A30P and A53T mutations of the presynaptic protein -synuclein are associated with familial forms of Par-kinson disease. NMR spectroscopy demonstrates that Parkinsonism-linked mutations greatly perturb specific tertiary interactions essential for the native state of -synuclein. However, -synuclein is not completely un-folded but exhibits structural fluctuations on the time scale of secondary structure formation and loses its native conformation gradually when protein stability decreases. The redistribution of the ensemble of -synuclein conformers may underlie toxic gain-of-func-tion by fostering self-association and altered binding affinity to ligands and receptors. Parkinson disease (PD)1 is the most common neurodegenera-tive movement disorder and is characterized by the loss o