The Neurotoxic Properties of α-synuclein Polymorphs

Progressive neurodegeneration is a common pathological feature of synucleinopathies, which include dementia with Lewy bodies (DLB), Parkinson's disease (PD), and multiple system atrophy (MSA). Among mechanisms known to induce neurodegeneration, the presence of aggregated forms of α-synuclein (α-syn) has been extensively considered as a causal factor for cell death. These aggregates exist in multiple different physical forms, which might yield different disease phenotypes and explain the heterogeneity among these diseases. Here, we investigated the neurotoxic properties of structurally distinct and exogenous α-syn polymorphs. Most of the polymorphs at the concentrations we studied are neurotoxic, but dopamine stabilized α-syn oligomer induced greater levels of neurotoxicity at lower concentrations compared to other polymorphs. In addition, polymorphs commonly induced apoptotic neuronal death through autophagic impairment. Our results suggest that neurons have different sensitivities to different α-syn aggregates, which should be a consideration when developing disease markers and therapeutics.