Abstract
In Parkinson's disease, intracellular α-synuclein (α-syn) inclusions form in neurons and are referred to as Lewy bodies. These aggregates spread through the brain following a specific pattern leading to the hypothesis that neuron-to-neuron transfer is critical for the propagation of Lewy body pathology. Here we review recent studies employing pre-formed fibrils generated from recombinant α-syn to evaluate the uptake, trafficking, and release of α-syn fibrils. We outline methods of internalization as well as cell surface receptors that have been described in the literature as regulating α-syn fibril uptake. Pharmacological and genetic studies indicate endocytosis is the primary method of α-syn internalization. Once α-syn fibrils have crossed the plasma membrane they are typically trafficked through the endo-lysosomal system with autophagy acting as the dominant method of α-syn clearance. Interestingly, both chaperone-mediated autophagy and macroautophagy have been implicated in the degradation of α-syn, although it remains unclear which system is chiefly responsible for the removal of α-syn fibrils. The major hallmark of α-syn spreading is the templating of misfolded properties onto healthy protein resulting in a conformational change; we summarize the evidence indicating misfolded α-syn can seed endogenous α-syn to form new aggregates. Finally, recent studies demonstrate that cells release misfolded and aggregated α-syn and that these processes may involve different chaperones. Nonetheless, the exact mechanism for the release of fibrillar α-syn remains unclear. This review highlights what is known, and what requires further clarification, regarding each step of α-syn transmission.
Highlights
In Parkinson’s disease, intracellular α-synuclein (α-syn) inclusions form in neurons and are referred to as Lewy bodies. These aggregates spread through the brain following a specific pattern leading to the hypothesis that neuron-to-neuron transfer is critical for the propagation of Lewy body pathology
We outline methods of internalization as well as cell surface receptors that have been described in the literature as regulating α-syn fibril uptake
Both chaperone-mediated autophagy and macroautophagy have been implicated in the degradation of α-syn, it remains unclear which system is responsible for the removal of α-syn fibrils
Summary
The hypothesis that α-synuclein (α-syn) pathology is propagated along neuronal pathways and by intercellular exchange implies at least three physiological processes: membrane binding and internalization by recipient cells, interaction with intracellular α-syn, and eventual secretion or transport into adjacent cells. Different mechanisms for internalization have been proposed including endocytosis, micropinocytosis, and cell surface protein-mediated uptake (Figure 1). In non-neuronal cell lines, α-syn fibrils bind to heparan sulfate chains in the plasma membrane prior to internalization (Holmes et al, 2013).
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