The Role of α-Synuclein Oligomers in Parkinson's Disease

Abstract

α-synuclein (α-syn) is a protein associated with the pathogenesis of Parkinson's disease (PD), the second most common neurodegeneration disease with no effective treatment. However, how α-syn drives the pathology of PD remains elusive. Recent studies suggest that α-syn oligomers are the primary cause of neurotoxicity and play a critical role in PD. In this review, we discuss the process of α-syn oligomers formation and the current understanding of the structures of oligomers. We also describe seed and propagation effects of oligomeric forms of α-syn. Then, we summarize the mechanism by which α-syn oligomers exert neurotoxicity and promote neurodegeneration, including mitochondrial dysfunction, endoplasmic reticulum stress, proteostasis dysregulation, synaptic impairment, cell apoptosis and neuroinflammation. Finally, we investigate treatment regimens targeting α-syn oligomers at present. Further research is needed to understand the structure and toxicity mechanism of different types of oligomers, so as to provide theoretical basis for the treatment of PD.

Keywords: Parkinson’s disease; oligomers; structure; toxicity; α-synuclein.

Figure 1

The process of α-syn aggregation. Under physiological conditions, α-syn exists as unfolded monomers, in equilibrium with membrane-bound species that promote SNARE-complex assembly and tetramers that can resist abnormal aggregation. When the balance between α-syn generation and clearance is disrupted, the monomers aggregate to form oligomers, including on-pathway oligomers and off-pathway oligomers. On-pathway oligomers tend to form protofibrils, and eventually fibrils. Other oligomers that cannot form amyloid fibrils are called off-pathway oligomers.

Figure 2

Current understanding of the structure of α-syn oligomers. (A) Structure of α-syn oligomers obtained by small angle X-ray scattering. The oligomer exhibits a 180 Å long and 90 Å wide circular shape with a cavity in the middle. (B,C) Structures of two subgroups of oligomers revealed by cryo-electron microscopy. Both subgroups have hollow cylindrical structures. (A) Adapted with permission from Reference [23], Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 3246-3251. (B,C) Adapted with permission from Reference [24], Proc. Natl. Acad. Sci. U.S.A. 2015, 112, E1994-2003.

Figure 3

The mechanism of α-syn oligomers neurotoxicity. α-syn oligomers showing neurotoxic effects through multiple ways. Mitochondrial dysfunction can be triggered by α-syn oligomers through mitochondrial complex impairment and other kinds of mechanisms. Oligomeric α-syn uniquely lead to ER stress. The two main ways to maintain proteostasis, UPS and ALP, which are both affected by α-syn oligomers. Oligomers inhibit proteasome activity and cause lysosome dysfunction. α-syn is abundant in synapse while pathological α-syn oligomers damage synapse function via inhibiting SNARE complex formation and dopamine release. Some mutant α-syn oligomers have the ability to impair axon transport. α-syn oligomers also bind to NMDA receptor, resulting in membrane damage and LTP impairment. In addition to the direct cytotoxic effects on neurons, α-syn also participates in PD pathology by activating glial cells through toll-like receptor, giving rise to secretion of pro-inflammatory cytokines and neuron loss.

Figure 4

Therapies targeting α-syn oligomers. Natural compounds, heat shock proteins and molecular tweezers reduce the level of toxic oligomers. Oligomer-specific antibodies neutralize certain kinds of α-syn oligomers. Receptor antagonist prevents the oligomers from binding to the receptors and exhibiting cytotoxicity.