Converse modulation of toxic alpha-synuclein oligomers in living cells by N'-benzylidene-benzohydrazide derivates and ferric iron.
Converse modulation of toxic alpha-synuclein oligomers in living cells by N'-benzylidene-benzohydrazide derivates and ferric iron.
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DOI：
10.1016/j.bbrc.2009.11.080
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发表时间：
2010-01-01
影响因子：
3.1
通讯作者：
Giese, Armin
中科院分区：
文献类型：
--
作者：
Hillmer, Andreas S.;Putcha, Preeti;Levin, Johannes;Hoegen, Tobias;Hyman, Bradley T.;Kretzschmar, Hans;McLean, Pamela J.;Giese, Armin
关键词：
细胞内α-突触核蛋白（α-syn）聚集物是多种神经退行性疾病的病理标志，包括帕金森病、路易体痴呆和多系统萎缩。最近的证据表明，在这些疾病中，小的寡聚物聚集体而不是大的淀粉样原纤维代表了主要的有毒颗粒种类。我们最近利用共聚焦单分子荧光技术表征了铁依赖性毒性α-syn低聚物物种，并利用该聚集模型在体外鉴定了几种抑制低聚物形成的N ' -苄基-苯并肼（NBB）衍生物。在我们目前的工作中，我们使用生物发光蛋白片段互补法（BPCA）直接分析了细胞培养中毒性α-syn低聚物的形成，并研究了铁和潜在的药物样化合物在活细胞中的作用。与我们之前在体外的研究结果相似，我们发现NBB衍生物和铁对有毒α-syn低聚物有相反的调节作用，其特征是铁增加了聚集体的形成，并对某些NBB化合物有抑制作用。NBB化合物293G02抑制α-syn低聚物的形成与细胞毒性的降低是平行的，这表明在BPCA细胞培养模型中存在有毒的α-syn低聚物，并且药物抑制低聚物的形成可以降低毒性。因此，该方法为开发针对毒性低聚物的新型疾病修饰药物提供了合适的模型系统。此外，NBB化合物如293G02可能提供有用的工具化合物来剖析有毒低聚物物种在细胞培养模型和体内的功能作用。
Intracellular α-synuclein (α-syn) aggregates are the pathological hallmark in several neurodegenerative diseases including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Recent evidence suggests that small oligomeric aggregates rather than large amyloid fibrils represent the main toxic particle species in these diseases. We recently characterized iron-dependent toxic α-syn oligomer species by confocal single molecule fluorescence techniques and used this aggregation model to identify several N′-benzylidene-benzohydrazide (NBB) derivatives inhibiting oligomer formation in vitro. In our current work, we used the bioluminescent protein-fragment complementation assay (BPCA) to directly analyze the formation of toxic α-syn oligomers in cell culture and to investigate the effect of iron and potential drug-like compounds in living cells. Similar to our previous findings in vitro, we found a converse modulation of toxic α-syn oligomers by NBB derivates and ferric iron, which was characterized by an increase in aggregate formation by iron and an inhibitory effect of certain NBB compounds. Inhibition of α-syn oligomer formation by the NBB compound 293G02 was paralleled by a reduction in cytotoxicity indicating that toxic α-syn oligomers are present in the BPCA cell culture model and that pharmacological inhibition of oligomer formation can reduce toxicity. Thus, this approach provides a suitable model system for the development of new disease-modifying drugs targeting toxic oligomer species. Moreover, NBB compounds such as 293G02 may provide useful tool compounds to dissect the functional role of toxic oligomer species in cell culture models and in vivo.
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影响因子：
56.9
作者：
Singleton, AB;Farrer, M;Gwinn-Hardy, K
通讯作者：
Gwinn-Hardy, K
影响因子：
4.8
作者：
Schiffer, Niclas W.;Broadley, Sarah A.;Schmid, Bettina
通讯作者：
Schmid, Bettina
影响因子：
3.7
作者：
Outeiro TF;Putcha P;Tetzlaff JE;Spoelgen R;Koker M;Carvalho F;Hyman BT;McLean PJ
通讯作者：
McLean PJ
DOI：
10.1073/pnas.96.24.13756
发表时间：
1999-11-23
影响因子：
11.1
作者：
Kask, P;Palo, K;Gall, K
通讯作者：
Gall, K
DOI：
10.1073/pnas.97.10.5468
发表时间：
2000-05-09
影响因子：
11.1
作者：
Bieschke, J;Giese, A;Kretzschmar, H
通讯作者：
Kretzschmar, H