Loss of Functional Alpha-Synuclein: A Toxic Event in Parkinson's Disease?

The discovery that alpha-synuclein (alpha-syn) is the primary component of the neuropathological hallmarks of Parkinson's disease (PD) and the identification of alpha-syn mutations in numerous inherited forms of PD has positioned alpha-syn at the top of the list of important factors in the pathogenesis of PD. Based on the pathological accumulation of alpha-syn in the brains of patients, the field is currently focused on therapeutic strategies that aim to reduce or eliminate alpha-syn. However, recent evidence suggests alpha-syn is a critical protein in neuron (i.e. dopamine neurons) survival and that maintaining a certain level of biologically functional alpha-syn is an important consideration in targeting alpha-syn for therapies. Despite the widespread interest in alpha-syn, the normal biological functions remain elusive, but a large body of work is focused on addressing this issue. In this review, we will discuss the current evidence related to alpha-syn function, alpha-syn folding and aggregation, and alpha-syn's role in disease. Finally, we will propose a relatively novel hypothesis on the pathogenesis of PD that hinges upon the premises that functional alpha-syn is critical to cell survival and that a reduction in biologically functional alpha-syn, whether through aggregation or reduced expression, may lead to the neurodegeneration in PD.