The Emerging Role of α-Synuclein Strains in Parkinson’s Disease: From Molecular Pathology to Clinical Phenotypes

Progressive loss of dopaminergic neurons and the formation of α-synuclein aggregates are hallmarks of Parkinson's disease.Biochemical, biophysical, cellular, animal, and clinical studies provide increasing evidence that α-synuclein is a highly "heterogeneous protein" that may exist in nature in different conformational states or "strains."The various strains differ biochemically and biophysically, elicit different seeding activities in cell culture assays, and have distinct pathological and cellular effects.The ability of different α-synuclein strains to seed and propagate themselves through host cells could explain the ability of misfolded α-synuclein to act as a prion-like agent, spread from neuron to neuron, and cause disease.Notably, different α-synuclein strains can have different abilities to propagate in cell culture and animal models of Parkinson's disease.Moreover, specific α-synuclein strains may induce similar motor, cognitive, psychiatric, and autonomic signs and symptoms of human Parkinson's disease.The heterogeneity of αsynuclein strains may, therefore, contribute to the variety of clinical presentations of the disease.However, the clinical associations of specific α-synuclein strains are mostly indirect and based on correlational studies.Thus, α-synuclein strains might serve as useful biomarkers of disease prognosis and stratification, although the evidence for their role in Parkinson's disease is still limited.At the same time, there are significant methodological limitations to current approaches used for characterizing α-synuclein strains, and much work remains to be done before α-synuclein strains can be reliably used to predict patient outcomes.