Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

Abstract

The accumulation of misfolded alpha-synuclein (aSyn) throughout the brain, as Lewy pathology, is a phenomenon central to Parkinson's disease (PD) pathogenesis. The stereotypical distribution and evolution of the pathology during disease is often attributed to the cell-to-cell transmission of aSyn between interconnected brain regions. The spreading of conformationally distinct aSyn protein assemblies, commonly referred as strains, is thought to result in a variety of clinically and pathologically heterogenous diseases known as synucleinopathies. Although tremendous progress has been made in the field, the mechanisms involved in the transfer of these assemblies between interconnected neural networks and their role in driving PD progression are still unclear. Here, we present an update of the relevant discoveries supporting or challenging the prion-like spreading hypothesis. We also discuss the importance of aSyn strains in pathology progression and the various putative molecular mechanisms involved in cell-to-cell protein release. Understanding the pathways underlying aSyn propagation will contribute to determining the etiology of PD and related synucleinopathies but also assist in the development of new therapeutic strategies.

Keywords: Parkinson’s disease; alpha-synuclein; cell-to-cell transfer; neurodegeneration; prion-like spreading.

Figure 1

Model for templated misfolding of endogenous alpha-synuclein (aSyn). Under pathological conditions, due to genetic or environmental factors, natively unfolded aSyn monomers are able to self-aggregate in pathological oligomers. These species can be extended into protofibrils and other mature species such as fibrils or ribbons that deposit into inclusion bodies as Lewy bodies (LBs) and Lewy neurites (LNs). Although the biophysical properties and formation of ribbons are still not well understood, the other aSyn assemblies coexist in a dynamic equilibrium and can be transformed into higher- or lower-order conformations.

Figure 2

Schematic representation of the possible molecular mechanisms involved in the cell-to-cell transmission and progression of aSyn pathology in Parkinson’s disease (PD). Release of aSyn to the extracellular space can occur via exocytosis/direct translocation through the plasma membrane from a donor to a recipient cell (blue cell). Additionally, misfolded-associated protein secretion pathway (MAPS) is also used to preferentially export aberrant cytosolic proteins. In this mechanism, the endoplasmic reticulum (ER)-associated deubiquitylase USP19 recruits misfolded proteins to the ER surface for deubiquitylation. Then, these cargoes are encapsulated into ER-associated late endosomes and secreted to the extracellular space. Exosomes are derived from multivesicular bodies (MVBs) and have been reported to mediate aSyn release from cells. Tunneling nanotubes (TNTs) can form a direct connection between two cells possibly allowing aSyn from one cell to another. The entry of aSyn into the receptor cell can occur via passive diffusion through the plasma membrane, endocytosis, receptor-mediated endocytosis, and exosome-mediated transfer (orange cell). Furthermore, a high concentration of aSyn in the membrane potentiates its oligomerization and the putative formation of trans-membrane amyloid pores (these pores have yet to be identified in human brain tissue). Last, dying neurons will release their content into the extracellular space, which is another potential source of extracellular aSyn (gray cell).