Alpha-synuclein: Implications for Parkinson's Disease

Abstract and Introduction

Abstract

The critical role of alpha-synuclein in Parkinson's disease represents a pivotal discovery. Some progress has been made over recent years in identifying disease-modifying therapies for Parkinson's disease that target alpha-synuclein. However, these treatments have not yet shown clear efficacy in slowing the progression of this 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 over recent years to study the physiological and pathological roles 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 modelling 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 of dissecting the 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 that occur 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.

Introduction

Mutations in the gene that codifies alpha-synuclein (α-syn) cause Parkinson's disease (PD).^[1] This discovery of a genetic defect leading to PD opened new avenues for investigating the molecular basis of the disorder,^[2] and it is now clear that this protein also plays a critical role in the sporadic forms of PD.

Some progress has been made over recent years in identifying disease-modifying therapies for PD that target α-syn.^[3] However, these treatments have not yet fully met the required end point, including a disease-modifying effect.^[4–6] Several explanations exist for this failure. First, the pathogenesis of PD is complex and not yet fully clarified. Thus, the ideal target and time window for treatment are unknown. Second, the heterogeneity of the disease, with diverse genetic susceptibility and risk factors and different clinical courses, adds further complexity.

Another obstacle to an effective α-syn-related disease-modifying therapy might be the lack of specificity of these approaches in distinguishing between the detrimental effects of the protein and its physiological functions. The need to dissect these aspects is emerging, along with the concept of proteinopenia versus proteinopathy, concerning the role of α-syn in PD.^[7] In this review, we explain how these roles are intermingled at the synaptic level. Although the physiological function of α-syn is yet to be fully elucidated, this protein is enriched in presynaptic compartments, where it can associate with vesicles and membranes.^[8] The synapse is also the scenario in which pathological α-syn exerts its early detrimental effects, preventing vesicle clustering and altering postsynaptic responses to transmitters, which in turn cause impairment of synaptic plasticity.^[9] This cascade of early abnormal events might be responsible for a network dysfunction before the occurrence of overt neurodegeneration.

We will evaluate new advances in the understanding of synaptic changes modulated by α-syn that occur before neuronal death and how they influence synaptic plasticity in the basal ganglia and other brain networks. Moreover, we will discuss how and why these new findings support the idea that any new therapeutic approaches should target synaptopathy and indicate that future studies across multiple neuron types and circuits are mandatory.