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.
Highlights
Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder related to aging worldwide [1]
Some mechanisms are triggered by the phosphorylation of α-synuclein, including the unfolded protein response (UPR) and disruption of lysosomal degradation pathways, which may lead to protein aggregation and subsequently to cell death (Figure 2) [78, 79]
Concluding Remarks α-Synuclein is a highly relevant protein in PD etiopathology, and since the elucidation of α-synuclein-copper interactions, this transition metal was brought into the spotlight of neurodegeneration research
Summary
Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder related to aging worldwide [1]. Once the accumulation of α-synuclein surpasses its degradation rate, it leads to the formation of Lewy bodies and the subsequent death of dopaminergic neurons in the substantia nigra [41]. Studies performed in cell cultures with neuronal phenotype have demonstrated that CK2-mediated α-synuclein phosphorylation, at S129, increases the appearance of eosinophilic cytoplasmic inclusions resembling the Lewy bodies of PD [76]. Some mechanisms are triggered by the phosphorylation of α-synuclein, including the unfolded protein response (UPR) and disruption of lysosomal degradation pathways, which may lead to protein aggregation and subsequently to cell death (Figure 2) [78, 79]. It has been reported that α-synuclein can be phosphorylated by LK6 and Mnk2a, with subsequent dopaminergic neuronal death and formation of cytoplasmic inclusions, respectively [75]. A marked difference between PD patients and healthy controls was observed with a sensitive and specific Elisa test, by combining measurements of total, oligomeric, and phosphorylated (S129) αsynuclein in CSF [99]
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