Phosphorylated α-Synuclein-Copper Complex Formation in the Pathogenesis of Parkinson’s Disease

Figure 3

-Synuclein-copper complex formation process. Copper can be found in living organisms in both forms, oxidized Cu²⁺ and reduced Cu⁺, and enters into the cell as Cu⁺ through CTR1 and CTR2. Afterwards, copper is transported to the nuclei, endoplasmic reticulum, and mitochondria via chaperone proteins. An overload of copper may lead to the α-synuclein-copper complex formation by three potential mechanisms. In the first one, a single α-synuclein molecule binds to Cu²⁺, folding and bringing together the amino and carboxy-terminal ends. The second mechanism involves two molecules of α-synuclein with a head-to-tail arrangement, generating a copper-binding site at both ends. In the third mechanism, the carboxy-terminal region of one molecule of α-synuclein interacts with the amino-terminal region from another molecule of α-synuclein creating a Cu²⁺ binding site. Next, one of the two α-synucleins interacts with a third α-synuclein molecule, forming a second Cu²⁺ binding site. This process will eventually lead to α-synuclein oligomerization.