Familial mutants of α-synuclein with increased neurotoxicity have a destabilized conformation

A30P and A53T mutations of the presynaptic protein alpha- synuclein are associated with familial forms of Parkinson disease. NMR spectroscopy demonstrates that Parkinsonism- linked mutations greatly perturb specific tertiary interactions essential for the native state of alpha- synuclein. However, alpha- synuclein is not completely unfolded 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 alpha- synuclein conformers may underlie toxic gain- of- function by fostering self- association and altered binding affinity to ligands and receptors.