RP7: Investigation of novel mechanisms in degradation of aggregated neuroserpin

加工不良的蛋白质的神经元积累是许多神经退行性疾病的标志，例如弥漫性路易体病、tau蛋白病和具有神经丝氨酸蛋白酶抑制剂包涵体的家族性脑病（FENIB）。这些疾病中的一些共享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蛋白酶抑制剂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所致。在第一个资助期内，我们能够概括FENIB小鼠模型的致病特征，如聚集、降解和神经退行性变。我们提案的目的是确定参与聚集神经元蛋白降解的组分。我们已经产生了一个秀丽隐杆线虫模型FENIB通过表达荧光标记，聚集倾向形式的神经丝氨酸蛋白酶抑制剂同系物SRP-2。该模型使我们能够筛选调节聚集的SRP-2的降解的新型调节剂和药理学物质，这将在哺乳动物细胞培养实验和转基因neuroserpin表达小鼠中进一步研究。这些研究的数据将是有价值的，在确定新的治疗策略，一般痴呆症。

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.