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

The discovery that alpha-synuclein (α-syn) is the primary component of the neuropathological hallmarks of Parkinson’s disease (PD) and the identification of α-syn mutations in numerous inherited forms of PD has positioned α-syn at the top of the list of important factors in the pathogenesis of PD. Based on the pathological accumulation of α-syn in the brains of patients, the field is currently focused on therapeutic strategies that aim to reduce or eliminate α-syn. However, recent evidence suggests α-syn is a critical protein in neuron (i.e. dopamine neurons) survival and that maintaining a certain level of biologically functional α-syn is an important consideration in targeting α-syn for therapies. Despite the widespread interest in α-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 α-syn function, α-syn folding and aggregation, and α-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 α-syn is critical to cell survival and that a reduction in biologically functional α-syn, whether through aggregation or reduced expression, may lead to the neurodegeneration in PD.