RP7: Investigation of novel mechanisms in degradation of aggregated neuroserpin

FP7：聚集神经丝氨酸蛋白酶抑制剂降解新机制的研究

• 批准号: 45605015
• 负责人: Professor Dr. Markus Glatzel
• 金额: --
• 依托单位: Institut für Genetik
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/45605015?language=en
• 关键词: RP7; Investigation; novel; mechanisms; degradation

Neuronal accumulation of mal-processed proteins is the hallmark of a number of neurodegenerative disorders such as diffuse Lewy body diseases, tauopathies and familial encephalopathy with neuroserpin inclusion bodies (FENIB). Some of these diseases share common pathways leading to neuronal death, which are linked to accumulation of proteins in specific intracellular compartments. Accumulation of malprocessed neuroserpin reflects a dynamic process, resulting from the disturbed balance between synthesis and degradation. During the first funding period we were able to recapitulate the pathogenic characteristics such as aggregation, degradation, and neurodegeneration in a mouse model for FENIB.The objective of our proposal is to identify components involved in the degradation of aggregated neuronal proteins. We have generated a Caenorhabditis elegans model for FENIB by expressing fluorescently tagged, aggregation-prone forms of the neuroserpin homolog SRP-2. This model allows us to screen for novel modulators and pharmalogical substances modulating the degradation of aggregated SRP-2, which will be further investigated in mammalian cell culture experiments and transgenic neuroserpin expressing mice. Data from these studies will be valuable in identifying novel therapeutical strategies for dementias in general.

不良加工蛋白的神经元积累是许多神经退行性疾病的标志，如弥漫性路易体病、牛头病和带有神经丝氨酸包涵体（FENIB）的家族性脑病。其中一些疾病具有导致神经元死亡的共同途径，这与特定细胞内区室中蛋白质的积累有关。加工不良的神经丝氨酸的积累反映了一个动态过程，这是由于合成和降解之间的平衡受到干扰而导致的。在第一个资助期，我们能够概括FENIB小鼠模型的致病特征，如聚集、降解和神经变性。我们建议的目的是确定参与降解聚集的神经元蛋白的成分。我们通过表达荧光标记的、易于聚集的神经丝氨酸蛋白同源物SRP-2，建立了秀丽隐杆线虫FENIB模型。该模型允许我们筛选调节聚合的SRP-2降解的新型调节剂和药物物质，这将在哺乳动物细胞培养实验和转基因神经丝氨酸蛋白表达小鼠中进一步研究。这些研究的数据将对确定痴呆症的新治疗策略有价值。