Seeking a mechanism for the toxicity of oligomeric α-synuclein

Abstract

In a number of neurological diseases including Parkinson's disease (PD), α-synuclein is aberrantly folded, forming abnormal oligomers, and amyloid fibrils within nerve cells. Strong evidence exists for the toxicity of increased production and aggregation of α-synuclein in vivo. The toxicity of α-synuclein is popularly attributed to the formation of "toxic oligomers": a heterogenous and poorly characterized group of conformers that may share common molecular features. This review presents the available evidence on the properties of α-synuclein oligomers and the potential molecular mechanisms of their cellular disruption. Toxic α-synuclein oligomers may impact cells in a number of ways, including the disruption of membranes, mitochondrial depolarization, cytoskeleton changes, impairment of protein clearance pathways, and enhanced oxidative stress. We also examine the relationship between α-synuclein toxic oligomers and amyloid fibrils, in the light of recent studies that paint a more complex picture of α-synuclein toxicity. Finally, methods of studying and manipulating oligomers within cells are described.

Figure 1

Location of disease-associated point mutations in α-synuclein, indicated by red stars.

Figure 2

Cellular effects of α-synuclein toxic oligomers, and potential links to oligomer properties. Inner shell: proposed properties of toxic oligomers. Middle shell: examples of molecular effects conferred by toxic oligomers. Outer shell: cellular systems disrupted by toxic oligomers. Edges of the box: pathological outcomes of neuron dysfunction. ER—endoplasmic reticulum. UPR—unfolded protein response.

Figure 3

Toxic α-synuclein oligomers in relation to the pathway of amyloid fibril formation. Toxic oligomers have been reported by different studies as being “on-pathway” or “off-pathway” to amyloid fibril formation. Covalent bonding by oxidative modifications may be involved in stabilizing toxic “off-pathway” oligomers. Non-toxic oligomers that are “off-pathway” are stabilized by pharmacological inhibitors of fibril formation, such as baicalein. Toxicity of oligomers is likely to be related to their high levels of β-sheet secondary structure. Additionally, it has been hypothesized that protofibril/fibril elongation may be toxic. Blue circles- Little or no β-structure; Red circles- High β-structure.