Defining the link between the Prion Protein and Copper

描述（由申请人提供）：朊病毒疾病，或传染性海绵状脑病（tse），是一类致命的神经退行性疾病，由于英国“疯牛病”的流行和最近这种疾病传播给人类的病例而引起了公众的极大兴趣。尽管人们对与致病性亚型（PrPsc）相关的疾病过程了解甚多，但细胞朊病毒蛋白（PrPc）的正常生理功能仍然难以捉摸。已经积累了大量证据支持PrPc在铜的运输和代谢中的作用。在本文中，我们将通过结构-功能分析和检查铜诱导的有丝分裂后神经元中PrPc的内吞反应，进一步剖析铜和PrPc之间的联系。将测量PrPc突变体PG14的铜结合特性，以了解与PG14相关的克雅氏病遗传形式背后的分子基础。最后，一种铜代谢遗传性疾病（门克斯病）的小鼠模型将被用来确定PrPc是否在维持铜稳态中发挥作用。

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.