Insights on the interaction of alpha-synuclein and metals in the pathophysiology of Parkinson's disease

Abstract

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder with severe consequences for patients and caregivers. In the last twenty years of research, alpha-synuclein (αSyn) emerged as a main regulator of PD pathology, both in genetic and sporadic cases. Most importantly, oligomeric and aggregated species of αSyn appear to be pathogenic. In addition, transition metals have been implicated in the disease pathogenesis of PD already for decades. The interaction of metals with αSyn has been shown to trigger the aggregation of this protein. Furthermore, metals can exert cellular toxicity due to their red-ox potential, which leads to the formation of reactive oxygen species, exacerbating the noxious effects of αSyn. Here we give a brief overview on αSyn pathology and the role of metals in the brain and then address in more detail the interaction of αSyn with three disease-relevant transition metals, iron (Fe), copper (Cu) and manganese (Mn). We also discuss possible therapeutic approaches for PD, which are based on these interactions, e.g. chelation therapy and anti-oxidative treatments. Not all mechanisms of alpha-synuclein-mediated toxicity and roles of metals are sufficiently understood. We discuss several aspects, which deserve further investigation in order to shed light on the etiopathology of the disease and enable the development of more specific, innovative drugs for the treatment of PD and other synucleinopathies.