Modeling the cellular fate of alpha-synuclein aggregates: A pathway to pathology

Abstract

Parkinson's disease is a progressive neurodegenerative disorder that is characterized by pathological protein inclusions that form in the brains of patients, leading to neuron loss and the observed clinical symptoms. These inclusions, containing aggregates of the protein α-Synuclein, spread throughout the brain as the disease progresses. This spreading follows patterns that inform our understanding of the disease. One way to further our understanding of disease progression is to model the discrete steps from when a cell first encounters an aggregate to when those aggregates propagate to new cells. This review will serve to highlight the recent progress made in the effort to better understand the mechanistic steps that determine how this propagation happens at the cellular level.

Figure 1.

Exogenous αSyn fibrils are internalized into the cell and trigger aggregation of endogenous αSyn monomers. A) Extracellular fibrils are able to interact directly with cell membranes as well as bind to several classes of surface glycoproteins. B) Binding of heparan sulfate proteoglycans (HSPGs), syndecans, N-linked glycans, or receptor proteins can trigger endocytosis of fibrils by various mechanisms. C) Once internalized in endosomes, fibrils are delivered to the lysosome, however they are resistant to proteolytic degradation and persist in the lysosomal pathway. D) Failure to degrade fibrils in the lysosome leads to leakage, allowing some fibrils to escape into the cytosol. Some aggregate species may also be able to penetrate directly through the lysosomal membrane. E) Monomeric αSyn exists in equilibrium between the unstructured, soluble state and the α-helical, vesicle-bound state. The free monomer is more prone to aggregation, so factors that alter this equilibrium can promote or inhibit αSyn aggregation. F) Soluble monomers in the cytosol can interact with fibrils released from the lysosome, or otherwise delivered into the cell, to seed the generation of more fibrils and increase the aggregate burden in the cell. G) As fibrils accumulate in the cell, they can trap other cellular components such as lipids, vesicles, organelles, and other proteins. These fibrils will also become decorate by various post-translational modifications such as phosphorylation and ubiquitination. This process leads to the formation of a mature LB inclusions.