Modulation of PrPSc aggregation by treatment with a signaling pathway inhibitor

Prion and prion-like diseases are characterized by the deposition of misfolded proteins or amyloid aggregates as internal inclusion or external plaques in the central nervous system. Prions consist of a pathogenic isoform (PrPSc) of the normal host protein (PrPC) causing transmissible degenerative neurological diseases. It is believed that PrPSc catalyses the conversion of PrPC into PrPSc and thus becomes self-propagating (infectious) aggregates. Importantly, both expression of PrPC and its conversion into PrPSc are considered necessary for prion-induced degeneration. How this conversion is regulated is still unknown. It has been proposed that posttranslational modifications of PrP may be a critical factor contributing to the aggregate conformation, co-factor interactions, and disease progression. Results from our lab indicate that treatment of infected cells with a compound that modulates the post-translational modification of PrP reduces its localization at the plasma membrane. However, whether this inhibition is associated with the formation of intracellular self-propagating aggregates is still unknown. Characterization of the impact of the inhibitor on the cellular alterations and PrPSc aggregates formation inside the scrapie-infected cells will help us to determine the potential impact of this modification on PrP-mediated neurodegenerative diseases.

朊病毒（Prion）与类朊病毒疾病以错误折叠蛋白质或淀粉样蛋白聚集物在中枢神经系统内形成胞内包涵体或胞外斑块为特征。朊病毒由正常宿主蛋白（PrPC）的致病型同工型（PrPSc）构成，可引发传染性退行性神经系统疾病。学界普遍认为，PrPSc可催化PrPC转化为PrPSc，进而形成自我增殖（传染性）的聚集物。尤为关键的是，PrPC的表达及其向PrPSc的转化均被认为是朊病毒诱导神经元退行性变的必要条件。目前，该转化过程的调控机制仍不明晰。有研究提出，PrP的翻译后修饰可能是影响聚集物构象、辅因子相互作用及疾病进展的关键因素。本实验室的研究结果显示，采用可调控PrP翻译后修饰的化合物处理感染细胞，可降低其在质膜上的定位水平。但该抑制效应是否与胞内自我增殖聚集物的形成相关，目前仍未明确。阐明该抑制剂对瘙痒病感染细胞内细胞改变及PrPSc聚集物形成的影响，将有助于明确该修饰在PrP介导的退行性神经系统疾病中的潜在作用。