Alpha-synuclein in Parkinson's disease: A villain or tragic hero? A critical view of the formation of α-synuclein aggregates induced by dopamine metabolites and viral infection

Abstract

Introduction: Since the discovery of the presynaptic protein α-synuclein (aSyn) as a central player in Parkinson’s disease (PD), several key questions on the function of the protein in neurodegeneration processes remain unclear, including: is there a synergy between dopamine metabolism and the formation of toxic aSyn species in neurons? What is the role of aSyn in the immunological system? Areas covered: Herein, the authors revisit the intricate pathways related to dopamine metabolism and how it impacts on aSyn aggregation/function. Additionally, they discuss the importance of aSyn in the immune response to viral infections as well as the current findings on the possible protective role of certain virus vaccines against PD and other neuropathologies. Expert opinion: The physiological function of aSyn seems to cover different pathways, such as immune response against infections and a neuroprotective role, besides the already-established regulation of synaptic vesicle trafficking. Clinical studies with monoclonal antibodies against aSyn aggregates have shown disappointing results in patients with early-stage PD. Alternatively, we could consider, as immunological target, specific neurotoxic oligomers of aSyn formed in the presence of dopamine metabolites, such as DOPAL. Nevertheless, the crucial question remains as to whether removing these protein deposits will affect the clinical course of the disease.