Dopamine Affects the Stability, Hydration, and Packing of Protofibrils and Fibrils of the Wild Type and Variants of -Synuclein

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• 作者：Cristian Follmer ; Luciana Rom&atilde ; o ; Carla M. Einsiedler ; Thaí ; s C. R. Porto ; Flá ; vio Alves Lara ; Marlos Moncores ; Gilberto Weissmü ; ller ; Hilal A. Lashuel ; Peter Lansbury ; Vivaldo M
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：January 16, 2007
• 年：2007
• 卷：46
• 期：2
• 页码：472 - 482
• 全文大小：676K
• 年卷期：v.46,no.2(January 16, 2007)
• ISSN：1520-4995

文摘

Parkinson's disease (PD) is characterized by the presence of cytoplasmic inclusions composedof -synuclein (-syn) in dopaminergic neurons. This suggests a pivotal role of dopamine (DA) on PDdevelopment. Here, we show that DA modulates differently the stability of protofibrils (PF) and fibrils(F) composed of wild type or variants of -syn (A30P and A53T) as probed by high hydrostatic pressure(HHP). While in the absence of DA, all -syn PF exhibited identical stability, in its presence, the variant-composed PF acquired a greater stability (DAPF_wt < DAPF_A30P = DAPF_A53T), implying that they wouldlast longer, which could shed light onto why these mutations are so aggressive. When -syn was incubatedfor long times (18 days) in the presence of DA, we observed the formation of F by electronic microscopy,suggesting that the PF trapped in the presence of DA in short times can evolve into F. The stability of Fwas also altered by DA. DAF_wt was more labile than F_wt, indicating that the former would be moresusceptible to breakage. PF_A30P and DAPF_A30P, when added to mesencephalic and cortical neurons inculture, decreased the number and length of neurites and increased the number of apoptotic cells.Surprisingly, these toxic effects of PF_A30P and DAPF_A30P were practically abolished with HHP treatment,which was able to break the PF into smaller aggregates, as seen by atomic force microscopy. Theseresults suggest that strategies aimed at breaking and/or clearing these aggregates is promising in alleviatingthe symptoms of PD.