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

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