Advances in understanding of the function of alpha-synuclein: implications for Parkinson's disease

: The critical role of alpha-synuclein in Parkinson's disease represents a pivotal discovery. Some progress has been made in recent years in identifying disease-modifying therapies for Parkinson's disease that target alpha-synuclein. However, these treatments did not clearly show efficacy yet in slowing down the progression of Parkinson's disease. Several explanations exist for this issue. The pathogenesis of Parkinson's disease is complex and not yet fully clarified and the heterogeneity of the disease, with diverse genetic susceptibility and risk factors and different clinical courses, adds further complexity. Thus, a deep understanding of alpha-synuclein physiological and pathophysiological functions is crucial. In this review, we first describe the cellular and animal models developed in the last years to study the physiological and pathological role of this protein, including transgenic techniques, use of viral vectors and intracerebral injections of alpha-synuclein fibrils. We then provide evidence that these tools are crucial for modeling Parkinson's disease pathogenesis, causing protein misfolding and aggregation, synaptic dysfunction, brain plasticity impairment and cell-to-cell spreading of alpha-synuclein species. In particular, we focus on the possibility to dissect pre- and postsynaptic effects of alpha-synuclein, in both physiological and pathological conditions. Finally, we show how vulnerability of specific neuronal cell types may facilitate systemic dysfunctions leading to multiple network alterations. These functional alterations underlie diverse motor and non-motor manifestations of Parkinson's disease, occurring before overt neurodegeneration. However, we now understand that therapeutic targeting of alpha-synuclein in Parkinson's disease patients requires caution since this protein exerts important physiological synaptic functions. Moreover, the interactions of alpha-synuclein with other molecules may induce synergistic detrimental effects. Thus, targeting only alpha-synuclein might not be enough. Combined therapies should be considered in the future