Effects of nanoparticles on structure and function of the cell nucleus: Analysis of nuclear protein aggregation and neurodegeneration.

纳米粒子对细胞核结构和功能的影响：核蛋白聚集和神经变性的分析。

• 批准号: 195436142
• 负责人: Professorin Dr. Anna von Mikecz
• 金额: --
• 依托单位: Leibniz-Institut für umweltmedizinische Forschung (IUF)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/195436142?language=en
• 关键词: Effects; nanoparticles; structure; function; cell

The exponentially growing application of nanoparticles (NPs) in engineering and biomedicine calls for analysis of their interactions with cells and whole organisms in order to develop sustainable nanotechnologies. We showed previously that silica-NPs induce neurodegenerative phenotypes in cell culture and the nematode Caenorhabditis elegans. In cell culture silica-NPs cause formation of intranuclear protein aggregates. These inclusions form amyloid-like structures and recapitulate exactly polyglutamine-induced protein aggregation that occurs in neurodegenerative disorders such as Huntington's disease. Silica-NPs enabled demonstration that aggregation of endogenous nuclear proteins activates the ubiquitin-proteasome system, and amyloid-like aggregates represent sites of protein degradation. In contrast, titanium dioxide-NPs induce nuclear inclusions which are correlated with genotoxicity rather than altered proteostasis. Based on these results the main aim of the proposed project is to study the consequences of intranuclear protein aggregation for nuclear function. To this end, biochemical properties of NP-induced aggregates will be analysed in correlation with processes such as replication, DNA damage, repair, transcription, and cell death. Aggregate profiling in correlation with nuclear function seeks to fill the existing gap of knowledge between formation of intranuclear inclusions, resulting aberrant protein-protein interactions and altered function in the nucleus as well as their role in neurodegeneration. The latter will be reinforced by in vivo analyses in Caenorhabditis elegans. Here, the questions will be addressed which neurons and neuroendocrine signalling pathways are targeted in silica-NP-induced defects of egg-laying, and if altered proteostasis and protein aggregation contributes to the malfunction of the egg-laying circuit, e.g. interaction between HSN neurons and vulval muscles. The expected findings are capable to promote both, a better understanding of the role of protein aggregation in neurodegenerative processes, and cellular interactions of NPs.

纳米粒子（NPs）在工程和生物医学中的应用呈指数级增长，需要分析它们与细胞和整个生物体的相互作用，以开发可持续的纳米技术。我们以前表明，二氧化硅纳米颗粒诱导细胞培养和线虫线虫小杆线虫神经退行性表型。在细胞培养中，二氧化硅纳米颗粒引起核内蛋白质聚集体的形成。这些内含物形成淀粉样结构，并精确地再现了在神经退行性疾病如亨廷顿病中发生的多聚谷氨酰胺诱导的蛋白质聚集。二氧化硅纳米颗粒能够证明内源性核蛋白的聚集激活泛素-蛋白酶体系统，淀粉样蛋白聚集体代表蛋白质降解的位点。相比之下，二氧化钛纳米颗粒诱导核包涵体，这与遗传毒性相关，而不是改变蛋白质稳态。基于这些结果，该项目的主要目的是研究核内蛋白质聚集对核功能的影响。为此，NP诱导的聚集体的生物化学性质将与诸如复制、DNA损伤、修复、转录和细胞死亡等过程相关地进行分析。与核功能相关的聚集体分析试图填补核内包涵体形成、导致异常蛋白质-蛋白质相互作用和核中改变的功能以及它们在神经变性中的作用之间的现有知识空白。后者将通过秀丽隐杆线虫体内分析得到加强。在这里，将解决的问题，其中神经元和神经内分泌信号通路的目标是在硅-NP-诱导的缺陷的产卵，如果改变蛋白质稳态和蛋白质聚集有助于产卵电路的故障，例如HSN神经元和外阴肌肉之间的相互作用。预期的发现能够促进两者，更好地理解蛋白质聚集在神经退行性过程中的作用，以及NP的细胞相互作用。