Molecular mechanisms of alpha-synuclein neurodegeneration

Abstract

alpha-Synuclein is an abundant highly charged protein that is normally predominantly localized around synaptic vesicles in presynaptic terminals. Although the function of this protein is still ill-defined, genetic studies have demonstrated that point mutations or genetic alteration (duplications or triplications) that increase the number of copies of the alpha-synuclein (SCNA) gene can cause Parkinson's disease or the related disorder dementia with Lewy bodies. alpha-Synuclein can aberrantly polymerize into fibrils with typical amyloid properties, and these fibrils are the major component of many types of pathological inclusions, including Lewy bodies, which are associated with neurodegenerative diseases, such as Parkinson's disease. Although there is substantial evidence supporting the toxic nature of alpha-synuclein inclusions, other modes of toxicity such as oligomers have been proposed. In this review, some of the evidence for the different mechanisms of alpha-synuclein toxicity is presented and discussed.

Figure 1. Amino acid sequence and regions of α-synuclein

α-Syn is composed of: 1) an amino-terminal domain (black) containing several imperfect KTKEGV motifs (blue underline); 2) a hydrophobic center (purple) termed non-amyloid component (NAC); and 3) a negatively charged carboxy-terminus (green). Three familial mutations in α-syn (red) have been identified in patients with PD.

Figure 2. Formation of α-synuclein polymeric intermediates and fibrils

α-Syn in native, monomeric form is mostly unstructured. Under certain conditions α-syn can undergo structural changes, resulting in β-pleated sheet formation. This form of α-syn can take two pathways, one which is off of the fibrillar pathway, and the other which will eventually form mature fibrils. The off-fibril pathway can result in the formation of annular or other forms of oligomers that will never develop into mature fibrils. The fibrillar pathway undergoes intermediate stages, which include protofibrils, before maturing into long strands and becoming LBs or LNs.