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

Abstract

Parkinson's disease is the second most important neurodegenerative disorder worldwide. It is characterized by the presence of Lewy bodies, which are mainly composed of α-synuclein and ubiquitin-bound proteins. Both the ubiquitin proteasome system (UPS) and autophagy-lysosomal pathway (ALS) are altered in Parkinson's disease, leading to aggregation of proteins, particularly α-synuclein. Interestingly, it has been observed that copper promotes the protein aggregation process. Additionally, phosphorylation of α-synuclein along with copper also affects the protein aggregation process. The interrelation among α-synuclein phosphorylation and its capability to interact with copper, with the subsequent disruption of the protein degradation systems in the neurodegenerative process of Parkinson's disease, will be analyzed in detail in this review.

Figure 1

Schematic structure of α-synuclein. (a) α-Synuclein mutations related to familial PD are shown as red squares. Metal-binding sites are depicted as yellow squares. Seine (S) and threonine (Y) amino acid residues targeted by phosphorylation are indicated as blue squares. (b) Amino acid composition of α-synuclein. Residues in blue represent copper-binding sites. Red squares indicate methionine 1 and histidine 50, which are independent anchoring sites for copper binding. Green squares show phosphorylation sites (Y125 and S129) related to an increased copper-binding capability.

Figure 2

Cell alterations involved in the aggregation process of α-synuclein. Damaged or unrequired proteins are regulated by both the proteasomal and lysosomal degradation pathways. UPS disruption leads to activation of the ALS and vice versa, as a compensation mechanism. Both mechanisms are affected in PD, which results in protein accumulation including α-synuclein and ubiquitin-bound proteins. Accumulation of unfolded or misfolded proteins into the endoplasmic reticulum activates the unfolded protein response. Mitochondrial dysfunction and oxidative stress are also interrelated and linked to the pathogenesis of PD. All these alterations are associated with the phosphorylation process of α-synuclein and increase α-synuclein oligomerization, leading to Lewy body formation and subsequent apoptotic cell death.

Figure 3

α-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.