Binding of Noradrenaline to native and intermediate states during fibrillation of α-Synuclein leads to the formation of stable and structured cytotoxic species

Parkinson’s disease is characterized by the deterioration of dopaminergic neurons of substantia nigra pars compacta along with a substantial loss of noradrenergic neurons of the locus coeruleus which is the major source of noradrenaline (NA) in the brain. We have investigated the interaction of NA with α-Synuclein, the major protein constituent of Lewy bodies that are the pathological hallmark of PD. It is expected that NA, like dopamine could bind to α-Syn and modulate its aggregation propensity and kinetics which could also contribute to the onset of PD. We have, thus, evaluated the thermodynamic parameters of interaction of NA with α-syn monomer as well as species formed at different stages during its fibrillation pathway and have investigated the conformational and aggregation properties using various spectroscopic and calorimetric techniques. Binding isotherms of NA with α-syn species formed at different time points in the pathway have been observed to be exothermic in nature suggesting hydrogen bond...