Abstract
Parkinson’s disease (PD) is a multifactorial movement disorder in which both genetic and especially environmental factors play important roles. Substantial evidence implicates the aggregation of α-synuclein, an abundant and conservative presynaptic brain protein with unknown function, as a critical factor in PD. Rare familial cases of PD are associated with the mutations A30P (Ala to Pro substitution at position 30), E46K (Glu to Lys substitution at position 46), and A53T (Ala to Thr substitution at position 53) in α-synuclein. The primary structure of α-synuclein is characterized by several unusual motifs, and this protein was shown to have two closely related homologues, β-synuclein and γ-synuclein. Under the physiologic conditions in vitro, α-synuclein is characterized by the lack of rigid well-defined 3-D structure (i.e., it belongs to the class of natively unfolded proteins). Intriguingly, α-synuclein is known to possess remarkable conformational plasticity. The structure of this protein depends dramatically on the environment, and a number of absolutely unrelated conformations have been observed, including a partially folded intermediate that is a key intermediate in aggregation and fibrillation, several oligomeric species, and fibrillar and amorphous aggregates. A number of factors that either accelerate or inhibit the rate of fibrillation in vitro have been described. Accelerators include environmental factors such as certain pesticides and metals, molecular crowding, and various natural and synthetic charged polymers. Inhibitors include high concentrations of stabilizers such as trimethylamine N-oxide (TMAO), certain catechols, rifampicin, baicalein, acidic lipid vesicles, and protein homologues (β- and γ-synucleins). Oxidation of the four methionine residues in α-synuclein leads to the abolishment of fibrillation, as does the nitration of tyrosine residues. There is a strong correlation between the conformation of α-synuclein (induced by various factors) and its rate of fibrillation. The aggregation process appears to be branched, with one pathway leading to fibrils and another to oligomeric intermediates that may ultimately form amorphous deposits. The molecular basis of Parkinson’s disease appears to be tightly coupled to the aggregation of α-synuclein and the factors that affect its conformation.
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Uversky, V.N. (2007). α-Synuclein Aggregation and Parkinson’s Disease. In: Uversky, V.N., Fink, A.L. (eds) Protein Misfolding, Aggregation, and Conformational Diseases. Protein Reviews, vol 6. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-36534-3_4
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