Alpha-synuclein: from secretion to dysfunction and death

Abstract

The aggregation, deposition, and dysfunction of alpha-synuclein (aSyn) are common events in neurodegenerative disorders known as synucleinopathies. These include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. A growing body of knowledge on the biology of aSyn is emerging and enabling novel hypotheses to be tested. In particular, the hypothesis that aSyn is secreted from neurons, thus contributing to the spreading of pathology not only in the brain but also in other organs, is gaining momentum. Nevertheless, the precise mechanism(s) of secretion, as well as the consequences of extracellular aSyn species for neighboring cells are still unclear. Here, we review the current literature and integrate existing data in order to propose possible mechanisms of secretion, cell dysfunction, and death. Ultimately, the complete understanding of these processes might open novel avenues for the development of new therapeutic strategies.

Figure 1

Schematic representation of the aSyn aggregation process. Monomeric forms of aSyn associate to form dimers and oligomers that grow into protofibrils and, finally, form mature fibrillar structures

Figure 2

Proposed mechanisms of aSyn secretion. aSyn can be secreted both in its monomeric or aggregated forms by non-classical exocytic or endocytic pathways. aSyn can be directly integrated into secretory vesicles and subsequently released by exocytosis (1). Alternatively, aSyn can be translocated to early endosomes. From early endosomes, aSyn protein can either be released to the extracellular space through the recycling endosome (2) or incorporated to intraluminal vesicles of multivesicular bodies (MBV). MVB cargo including aSyn can be directed to degradation by fusion with lysosomes or to secretion by fusion with the plasma membrane and release of exosomal vesicles (3). TGN=trans-Golgi network

Figure 3

The role of extracellular aSyn in neuroinflammation, neurotoxicity, and spread of pathology. aSyn can be actively secreted or released by dying neurons to the extracellular space. Extracellular aSyn can then activate surrounding astrocytes and microglia, eliciting glial pro-inflammatory activity. Upon activation microglia produce pro-inflammatory cytokines, nitric oxide, and reactive oxygen species, which may be toxic to neurons. aSyn can be directly transferred between neurons, leading to propagation of aSyn aggregation process and compromising the viability of the recipient neuron