Defining the link between the Prion Protein and Copper

描述(申请人提供)：Prion病，或传播性海绵状脑病(TSE)，是一种致命的神经退行性疾病，由于英国的疯牛病流行和最近这种疾病向人类传播的病例，已经引起了公众的极大关注。虽然与致病亚型(PrPsc)相关的疾病过程已知很多，但细胞PrPc的正常生理功能仍然难以捉摸。已有大量证据支持PrPc在铜的贩运和代谢中发挥作用。在这项建议中，铜和PrPc之间的联系将通过结构-功能分析和铜诱导的PrPc在有丝分裂后神经元中的内吞反应来进一步剖析。将测量PrPc突变体pG14的铜结合特性，以了解与pg14相关的可遗传形式克雅病背后的分子基础。最后，将使用一种遗传性铜代谢疾病(门克斯病)的小鼠模型来确定PrPc是否在维持铜的动态平衡中发挥作用。

DESCRIPTION (provided by applicant): Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a class of fatal neurodegenerative disorders that have acquired much public interest due to the epidemic of "mad cow disease" in Britain and recent cases of transmission of this disease to humans. Although much is known about the disease process associated with the pathogenic isoform (PrPsc), the normal physiological function of the cellular prion protein (PrPc) has remained elusive. Much evidence has accumulated supporting a role for PrPc in the trafficking and metabolism of copper. In this proposal, the link between copper and PrPc will be further dissected through a structure-function analysis and examination of the copper-induced endocytic response of PrPc in post-mitotic neurons. Copper binding properties of a mutant of PrPc, known as PG14, will be measured to gain an understanding of the molecular basis behind the PG14-associated heritable form of Creutzfeldt-Jakob disease. Finally, a mouse model of an inheritable disease of copper metabolism (Menkes disease) will be used to determine whether PrPc plays a role in the maintenance of copper homeostasis.