Alpha-Synuclein in Parkinson’s Disease: From Pathogenetic Dysfunction to Potential Clinical Application

Figure 1

Alpha-synuclein’s aggregation pathway and role as a diagnostic biomarker in PD. Alpha-synuclein is a small protein comprising 140 amino acids with three domains that exist in dynamic states. The α-helically folded tetramer is thought to be only adopted upon membrane binding. The three domains each have a role in aggregation, as shown in the figure. All known gene mutations are found in the N-terminal domain, and some have been proven to accelerate aggregation. The NAC domain has a stretch of 12 amino acid residues that are unique and typical in the formation of oligomers and fibrils. C-terminally truncated α-synuclein appears to aggregate faster. In addition, the phosphorylation of amino acid 129, located in C-terminal domain, plays a central role in the pathway and is promoted by PLK2. Alpha-synuclein leads to toxicity when aggregated into pathological oligomers, fibrils, and Lewy bodies. In the search for a diagnostic biomarker in PD, α-synuclein from the CSF, plasma, the submandibular gland, saliva, colonic and gastric mucosa samples, and peripheral nerve fibers has been tested.