کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2185084 | 1095959 | 2011 | 5 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Conserved C-Terminal Charge Exerts a Profound Influence on the Aggregation Rate of α-Synuclein Conserved C-Terminal Charge Exerts a Profound Influence on the Aggregation Rate of α-Synuclein](/preview/png/2185084.png)
α-Synuclein (α-syn) is the major component of filamentous Lewy bodies found in the brains of patients diagnosed with Parkinson's disease (PD). Recent studies demonstrate that, in addition to the wild-type sequence, α-syn is found in several modified forms, including truncated and phosphorylated species. Although the mechanism by which the neuronal loss in PD occurs is unknown, aggregation and fibril formation of α-syn are considered to be key pathological features. In this study, we analyze the rates of fibril formation and the monomer–fibril equilibrium for eight disease-associated truncated and phosphorylated α-syn variants. Comparison of the relative rates of aggregation reveals a strong monotonic relationship between the C-terminal charge of α-syn and the lag time prior to the observation of fibril formation, with truncated species exhibiting the fastest aggregation rates. Moreover, we find that a decrease in C-terminal charge shifts the equilibrium to favor the fibrillar species. An analysis of these findings in the context of linear growth theories suggests that the loss of the charge-mediated stabilization of the soluble state is responsible for the enhanced aggregation rate and increased extent of fibril fraction. Therefore, C-terminal charge is kinetically and thermodynamically protective against α-syn polymerization and may provide a target for the treatment of PD.
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Journal: Journal of Molecular Biology - Volume 411, Issue 2, 12 August 2011, Pages 329–333