The remarkable conformational plasticity of alpha-synuclein: blessing or curse?

• Alpha-synuclein aggregation is a critical event in Parkinson's disease pathogenesis.
• The nature of the toxic aggregate species remains controversial.
• Alpha-synuclein is a hub protein involved in divergent cellular pathways.
• Endogenous and exogenous factors modulate the alpha-synuclein aggregation process.
• Therapeutic approaches for Parkinson's disease targeting alpha-synuclein are in the pipeline.

The aggregation of the protein alpha-synuclein (α-SYN) is believed to be a critical event in Parkinson's disease (PD). α-SYN is characterized by a remarkable conformational plasticity, adopting different conformations depending on the environment. In vitro, α-SYN lacks a well-defined structure. Therefore, it was classified as an ‘intrinsically disordered protein’. A debate has recently begun over how α-SYN behaves in the cell: is it an intrinsically disordered protein or a stable tetramer with a low propensity for aggregation? In this review, we discuss the aggregation of α-SYN and describe factors that influence this process and their potential relevance in PD pathogenesis. We address the ways in which aggregated α-SYN mediates toxicity and might lead to PD, and propose possible therapeutic strategies.