Protein trapping leads to altered synaptic proteostasis in synucleinopathies.

Parkinson's disease (PD) is associated with the accumulation of alpha-synuclein (aSyn) in intracellular inclusions known as Lewy bodies and Lewy neurites. Under physiological conditions, aSyn is found at the presynaptic terminal and exists in a dynamic equilibrium between soluble, membrane-associated and aggregated forms. Emerging evidence suggests that, under pathological conditions, aSyn begins to accumulate and acquire a toxic function at the synapse, impairing their normal function and connectivity. However, the precise molecular mechanisms linking aSyn accumulation and synaptic dysfunction are still elusive. Here, we provide an overview of our current findings and discuss the hypothesis that certain aSyn aggregates may interact with proteins with whom aSyn normally does not interact with, thereby trapping them and preventing them from performing their normal functions in the cell. We posit that such abnormal interactions start to occur during the prodromal stages of PD, eventually resulting in the overt manifestation of clinical features. Therefore, understanding the nature and behaviour of toxic aSyn species and their contribution to aSyn-mediated toxicity is crucial for the development of therapeutic strategies capable of modifying disease progression in PD and other synucleinopathies.